高血压局部肾素血管紧张素系统与炎症因子关系及雌激素的影响
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摘要
目的：
在高血压病的发生发展过程中,严重的器官损伤可导致致命性的并发症。因此,逆转或减少靶器官损伤,防止并发症的发生是非常必要的。肾素血管紧张素系统和炎症在高血压靶器官损伤中可能扮演着重要的角色。女性激素可影响血压水平,对心血管系统具有一定的保护作用。本课题旨在研究性别对高血压局部RAS与炎症因子作用的影响。
方法与结果：
1.局部RAS、炎症与自发性高血压大鼠器官损伤
应用清醒自由活动大鼠血流动力学测定系统对WKY和SHR大鼠的血压、血压波动性进行监测,随后应用RT-PCR技术对局部组织中的TNF-α、IL-1β、IL-6及renin、ACE、ACE2、AT1、AT2进行检测,研究SHR心脏和主动脉中RAS各组分的基因表达；局部组织RAS的各种组分的基因表达与心血管肥大之间的关系；局部炎症因子对血管肥大的作用,以及其与局部RAS成分之间的关系。
1.1血流动力学变化、血浆AngⅡ的浓度、血清炎症因子的浓度及器官损伤
与WKY大鼠相比,在SHR中SBP、DBP及BPV明显增高,HP、HPV及BRS明显降低;血浆中AngⅡ的含量明显增高,血清IL-1β、IL-6的含量明显增高,SHR大鼠的器官损伤特点比较明显,主要表现在LVW/BW和AW/length明显增加。
1.2 RAS、炎症因子的mRNA在SHR心脏和主动脉中的表达
与WKY大鼠相比,SHR心脏中血管紧张素原、肾素、ACE2、AT1和AT2的mRNA表达分别增加了314%、212%、119%、215%和250%；WKY和SHR在心脏中ACE mRNA的表达无显著差异;SHR主动脉中ACE、ACE2、AT1和AT2的mRNA表达分别增加了116%、86%、107%和110%,WKY和SHR主动脉中血管紧张素原和肾素的mRNA表达无显著差异。
与WKY大鼠相比,SHR心脏中TNF-α、IL-1β和IL-6的mRNA表达分别增加了213%、132%和91%；与WKY大鼠相比,SHR主动脉中TNF-α和IL-6的mRNA表达分别增加了220%和458%,WKY和SHR主动脉中IL-1β的mRNA表达无显著差异。
1.3 SHR血浆中AngⅡ浓度和血流动力学参数与心脏和主动脉血管肥大的关系
BP和BPV与LVW/BW和AW/length之间呈显著正相关；而BRS与心血管肥大呈显著负相关。SHR血浆中AngⅡ浓度与LVW/BW和AW/length无显著相关。
1.4 SHR局部组织的RAS和炎症因子mRNA的表达与心脏血管肥大的关系
SHR心脏中ACE、ACE2和TNF-α的mRNA表达与LVW/BW之间呈显著正相关；而在主动脉中,血管紧张素原、ACE2、TNF-α、IL-6和IL-1β的mRNA表达与AW/length之间呈显著正相关。
1.5 SHR局部组织中RAS的mRNA表达与炎症因子mRNA表达之间的关系
SHR心脏中TNF-a的mRNA与肾素、AT1和AT2的mRNA表达之间呈显著正相关；主动脉中ACE2和AT2的mRNA表达与TNF-a的mRNA表达之间呈显著正相关。
SHR心脏中血管紧张素原、肾素、ACE、ACE2和AT2的mRNA表达与IL-6的mRNA表达之间呈显著正相关；主动脉中血管紧张素原、肾素、ACE2、AT1和AT2的mRNA表达与IL-6的mRNA表达之间呈显著正相关。
1.6多元逐步回归分析
DBP在LW/BW中的β=0.493,P<0.01,ACE基因表达的p=0.449,P<0.01。AW/length与BRS独立相关,β=-0.810,P<0.01。决定心血管损伤的平均共系数是0.596。这表明血流动力学因子、DBP、BRS以及ACE mRNA在高血压诱导的心血管肥大占59.6%的变异。
2.性别对自发性高血压大鼠炎症反应的作用研究
采用6月龄和12月龄的SHR,用无创尾动脉测压系统测定血压；麻醉后颈动脉插管取血样本,随后取器官样本,用放免法测定血浆AngⅡ、ET-1浓度,血清E2、TNF-α、IL-6和IL-1β浓度；大体观察靶器官损伤；应用RT-PCR技术检测肾脏组织中的TNF-α、IL-1β、IL-6的mRNA。
2.1性别对SHR的收缩压及靶器官损伤的影响
雄性SHR的SBP和体重明显高于同龄的雌性SHR,同性别的SHR随着年龄的增加,SBP和体重明显增加。同龄雌性SHR的VW/BW、LVW/BW和RVW/BW明显大于雄性组；同性别的雌性SHR随着年龄的增加,心室指数增大,同性别的雄性SHR随着年龄的增加,右心室指数增大。雄性SHR的LVW/RVW比值明显大于雌性,同性别的SHR随着年龄的增加,LVW/RVW增加。雄性SHRAW/length明显大于同龄雌性；同性别的SHR随着年龄的增加,AW/length增大。肾指数RKW/BW的性别二重性仅存在于12mSHR中,随着随着年龄的增加肾脏损伤加重。
2.2 SHR的AngⅡ、ET、E2及炎症因子的性别差异
在同龄异性SHR中,雄性组血浆AngⅡ的含量明显大于雌性组；雌性组血浆ET-1的量明显大于雄性组；均无年龄因素的影响。血清IL-1p：SHR-6m组明显高于同龄雄性组,雄性SHR-12m组明显高于同龄雌性组,SHR-12m组明显高于SHR-6m组。血清IL-6：雄性SHR组明显高于同龄的雌性组,SHR-12m组明显高于SHR-6m组。血清TNFα:SHR-6m不存在性别差异,雄性SHR-12m组明显高于同龄的雌性组；SHR-12m组明显高于SHR-6m组。
2.36月龄SHR的AngⅡ、ET与E2及炎症因子的相关性
SHR血浆AngⅡ与血清炎症因子IL-1p及IL-6之间呈正相关,而与TNF-α之间没有相关性；ET与各炎症因子之间没有相关性。雌性SHR血浆AngⅡ与血清E2之间呈正相关。
2.4 SHR肾组织中炎症因子mRNA表达
肾组织中IL-6 mRNA的表达：雌性SHR-6m组明显低于同龄雄性组(6m:53%,12m：272%)SHR-12m组明显高于同性别SHR-6m组(雌性：69%,雄性：242%)。IL-1p的mRNA的表达：SHR-12m组高于同性别SHR-6m组(雌性：25%,雄性：33%)。TNFa的mRNA的表达：雌性SHR-6m和SHR-12m明显低于同龄雄性(6m：54%,12m：50%),无年龄因素的影响。
3.性别对肾血管性高血压大鼠发生发展的影响
采用10周龄SD大鼠钳夹一侧肾动脉血管制备肾血管性高血压(2K1C),摘除一组雌性大鼠双侧卵巢(VOX)造成雌激素水平低下,再钳夹一侧肾动血管脉制备肾血管性高血压。常规饲养6个月,麻醉下股动脉插管测血压后,取血及器官。用ELISA法测定各组大鼠血浆中AngⅡ和ET-1的浓度,血清中炎症因子的浓度。观察靶器官损伤。应用Western Blot方法,检测各组大鼠胸主动脉、心脏和肾脏的组织中ACE、ACE2、AT1和AT2蛋白质表达。
3.12K1C大鼠血流动力学参数的测定
与2K1C-sham-雄性组比较,各2K1C手术组SBP、DBP显著性增高,而HP在2K1C-雌性组显著性降低,与2K1C-雄性组比较,2K1C-雌性组SBP、DBP显著性增高,2K1C-OVX组无差别,两组数据基本接近；与2K1C-雌性组比较,2K1C-OVX组SBP、DBP明显降低。
3.22K1C大鼠靶器官的测定
与2K1C-sham-雄性组比较,,VW/BW、LVW/BW、LVW/BW和RKW/BW均显著性增加；2K1C-雌性组的各项指标均明显高于2K1C-雄性组和2K1C-OVX组；AW/length仅在2K1C-雄性组显著升高,而在其他各组则无变化。
3.32K1C大鼠血浆AngII、ET-1和血清炎症因子浓度的测定
血浆AngⅡ:仅在2K1C-雄性组明显升高,而在其他各组均无差异。血浆ET-1：2K1C手术各组明显高于假手术组,并且2K1C-雌性组明显高于2K1C-雄性组和2K1C-OVX组。血清IL-1β:2K1C-OVX组升高,而2K1C-雌性组则是下降,其下降程度与2K1C-雄性组相比有显著性差异。血清IL-6：2K1C-OVX组减少,其他各组均无显著性变化；与2K1C-雌性组比较,2K1C-OVX组血清IL-6的浓度也明显减少。血清TNF-α:2K1C手术组明显升高；2K1C-OVX组升高作用最为明显。
3.4 2K1C大鼠组织中RAS蛋白表达的测定
血管组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE的蛋白表达2K1C-雄性组和2K1C-雌性组明显升高,2K1C-OVX组无变化,与2K1C-雄性组比较,2K1C-雌性组明显升高；ACE2蛋白表达2K1C-OVX组和2K1C-雌性组明显升高,2K1C-雄性组无变化；与2K1C-sham-雄性组比较,AT1受体的蛋白表达无差异,与2K1C-雄性组比较,2K1C-雌性组和2K1C-OVX组明显减少；AT2受体的蛋白表达各手术组明显增加,2K1C-雌性组增加最为明显。肾脏组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE蛋白的表达2K1C-雌性组明显升高；ACE2蛋白的表达各组间无统计学差异；AT1受体的蛋白表达2K1C-雌性组明显减少;AT2受体的蛋白表达2K1C-雄性组和2K1C-OVX组无统计学差异,2K1C-雌性组明显减少。心脏组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE蛋白的表达2K1C-雌性组升高；ACE2蛋白的表达2K1C-雄性组和2K1C-雌性组明显下降,两组间无差异；AT1受体的蛋白表达2K1C-雄性组和2K1C-雌性组增加,2K1C-雌性组与其他各组相比,AT1受体的蛋白表达明显增加。AT2受体的蛋白表2K1C-OVX组降低。
结论：
1.与血压正常的对照组比较,自发性高血压大鼠组的心脏和主动脉中RAS所有组分和炎性细胞因子的基因表达增加；左心室肥厚与心脏局部RAS的ACE和ACE2基因,TNF-α基因表达正相关相关；主动脉肥厚与主动脉局部RAS血管紧张素和ACE2基因,炎性细胞因子TNF-α、IL-1β和IL-6的基因表达呈正相关。ACE2和AT2在RAS中可能并没有起主要作用,但可部分对抗ACE和AT1在高血压靶器官损伤的作用。
2.雌激素对成年(6月龄)自发性高血压大鼠的血压水平和靶器官的损伤有一定的缓解作用；雌性成年组自发性高血压大鼠血浆AngⅡ明显低于同龄雄性组,ET-1明显高于同龄雄性组；血清中IL-6的浓度和肾组织中的mRNA表达显著低于同龄雄性组,并随着年龄的增长而增加；雌性老年组血清TNF-α的浓度,雌性成年组和老年组自发性高血压大鼠肾组织中TNF-αmRNA表达水平明显低于同龄雄性组；线性回归分析表明,IL-1β和IL-6均与AngⅡ呈显著正相关；雌二醇与AngⅡ呈显著正相关。
3)SD大鼠一侧肾动脉血管钳夹后,形成肾血管性高血压(2K1C)。2K1C雌性大鼠血压水平,心肌肥厚和肾脏损伤程度比2K1C雄性大鼠严重；双侧卵巢切除导致雌激素水平低下后,再钳夹一侧肾动脉血管,肾血管性高血压形成得严重程度轻与雌性大鼠,血压水平接近雄性大鼠；雌性2K1C大鼠肾血管性高血压严重程度的机制可能与促进ET-1的释放,明显升高心脏、胸主动脉和肾脏组织中ACE的蛋白表达,明显升高心脏组织中AT1受体的蛋白表达,而促进AngⅡ的作用有关。
Objective:
The development of hypertensive end organ damage(EOD)plays a pivotal role in the occurrence of hypertensive complications. It is therefore essential to reverse, reduce or prevent EOD from happening in the treatment of hypertension. Renin-angiotensin system may also play an important role in hypertensive EOD. Recently, an emerging concept contends that inflammation plays a predominant role in the progression of hypertension and is also involved in the triggering of hypertension-associated cardiovascular complications. Female sex hormones have the ability to affect blood pressure levels. Accumulating evidence from experimental studies showed that estrogens have a cardioprotective influence in women by improving endothelial function, and regulating the response to inflammation. Therefore, the present studyies were designed three parts to evealuatd the influence of estrogens on local renin-angiotensin system and inflammatory factors in hypertensive rats.
Methods and Results:
1. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats
SHR and WKY rats were used in this study. The blood pressure and baroreflex sensitivity were measured in conscious state. After hemodynamic monitoring and BRS studies, the animal was weighed, anesthetized, and killed by decapitation. The aorta and heart were immediately excised and rinsed in cold physiological saline for histopath-ological examination. The mRNA levels of angiotensinogen, renin, ACE, ACE2, AT1, AT2 in local tissue were determined using quantitative real-time polym-erase chain reaction. The plasma was collected for the determination of angiotensin II concentration using the radioimmunoassay kit. The main findings of this study are as following:
1.1 Hemodynamic parameter, plasma AngⅡ, serum inflammatory factors and EOD in SHR
Compared with WKY rats, BP, BPV, plasma AngⅡconcentration, serum IL-1βand IL-6 concentration were significantly higher, while HP, HPV and BRS were significantly lower in SHR. SHR present with obvious cardiovascular hypertrophy characterized by increased LVW/BW and AW/length.
1.2 mRNA expression of RAS and inflammatory factors in the heart and aorta of SHR
Compared with WKY rats, mRNA levels of angiotensinogen, renin, ACE2, AT1 and AT2 in the heart of SHR increased by 314%,212%,119%,215% and 250% respectively. There was no difference in ACE mRNA in the heart between SHR and WKY rats. mRNA levels of ACE, ACE2, AT1 and AT2 in the aorta of SHR increased by 116%,86%, 107% and 110% respectively when compared with those of WKY rats. There was no significant difference in angiotensinogen and renin mRNA in the aorta between SHR and WKY rats.
In addition, mRNA levels of TNFα, IL-1βand IL-6 in the heart of SHR increased by 213%,132% and 91% respectively, and mRNA levels of TNFa and IL-6 in the aorta of SHR increased by 220% and 458% respectively, when compared with WKY rats. There was no significant difference in IL-1βmRNA in the aorta between SHR and WKY rats.
1.3 Correlations between hemodynamics, plasma AngⅡconcentration, serum inflammatory factors and cardiovascular hypertrophy in SHR
BP and BPV were found to be positively correlated with LVW/BW and AW/length, while BRS was negatively correlated with cardiovascular hypertrophy. Plasma AngⅡwas insignificantly correlated with any cardiovascular damage parameter.
1.4 Correlations between local mRNA expression of RAS and inflammatory factors and cardiovascular damage in SHR
ACE, ACE2 and TNF-αmRNA expression in the heart was positively correlated with LVW/BW, while renin, ACE2, TNF-α, IL-1βand IL-6 mRNA expression in the aorta was also positively concerned with AW/length.
1.5 Relationships between local tissue RAS mRNA and inflammatory factor mRNA in SHR
Renin, AT1 and AT2 mRNA expression in the heart was positively correlated with TNF-αmRNA. ACE2 and AT2 mRNA expression in the aorta was also positively correlated with TNF-αmRNA.
Angiotensinogen, renin, ACE, ACE2 and AT2 mRNA expression in the heart was positively correlated with IL-6 mRNA. Angiotensinogen, renin, ACE2, AT1 and AT2 mRNA expression in the aorta was positively correlated with IL-6 mRNA
1.6 Stepwise multivariate regression analysis
The regression equations indicated that LV weight/BW was independently correlated with DBP(β=0.493, P< 0.01; whereβis the standardized partial regressive coefficient)and ACE gene expression(β=0.449, P<0.01). Aortic weight/length was independently correlated with BRS(β=-0.810, P<0.01). The determinant coefficient (R2) for cardiovascular damage averaged 0.596. This value means that the independent hemodynamic factors, DBP, BRS and ACE mRNA expression level explain 59.6% of the variation in the hypertensive cardiovascular hypertrophy.
2. Gender related influence on inflammatory factors in spontaneously hypertensive rats
Both male and female SHR rats were used in this study. The blood pressure was measured in conscious state by using the tail-cuff plethysmography method. The rats was anesthetized, and a polyether cannula (PE-50) was inserted into the carotid artery to collecting blood sample, the kidneys were collected and immediately frozen in liquid nitrogen. The aorta and heart were immediately excised and rinsed in cold physiological saline for histopathological examination. The mRNA levels of TNF-a, IL-1βand IL-6 in local tissue were determined using quantitative real-time polymerase chain reaction. The plasma was determined of angiotensinⅡ, ET-1 concentration, the serum of TNF-a, IL-1βand IL-6 concentration was determined by using the radioimmunoassay kit. The main finding of this study are as following:
2.1 Hemodynamic parameter, plasma AngⅡ, serum inflammatory factors and EOD in SHR
Compared with SHR-12m group, SBP and body weight(BW)were no change in SHR-6m group. SBP, BW, LVW/RVW and AW/length were significantly higher in the same age male SHR when compared with female SHR, and VW/BW, LVW/BW, RVW/BW were significantly lower in the same age male SHR. Compared with SHR-6m-female, VW/BW, LVW/RVW, RKW/BW and AW/length were significantly higher in the SHR-12m-female group. Compared with SHR-6m-male group, RVW/BW, LVW/RVW, RKW/BW and AW/length were significantly higher in the SHR-12m-male group.
2.2 plasma Ang II, ET-1 and serum inflammatory factors in SHR
Compared with female SHR, plasma AngⅡwas significantly higher in the male SHR, plasma ET-1 was significantly lower in the male SHR. The serum IL-1βwas significantly higher in the SHR-6m-female group than those of SHR-6m-male group, compared with SHR-12m-male group, serum IL-1βwas significantly lower in the SHR-12m-female group. Compared with SHR-male, serum IL-6 was significantly higher in the same age SHR-female, compared with SHR-6m group, serum IL-6 was significantly higher in the same sex SHR-12m group. serum TNF-αwas no significantly change in the SHR-6m group, compared with SHR-12m-male group, serum TNF-a was significantly lower in the SHR-12m-female group.
2.3 Correlations between plasma AngⅡ, ET-1 and serum inflammatory factors in SHR
Plasma Ang II was found to be positively correlated with serum IL-1βand IL-6. Plasma Ang II was positively correlated with serum E2. Plasma ET-1 was not any correlated with serum inflammatory factors in SHR.
2.4 mRNA expression of inflammatory factors in the kidney of SHR
group Compared with SHR-6m-female group, mRNA levels of IL-6 in the kidney of SHR-6m-male group increased by 53%, Compared with SHR-12m-female group, mRNA levels of IL-6 in the kidney of SHR-12m-male group increased by 272%. Compared with SHR-6m-male group, mRNA levels of IL-1βin the kidney of SHR-12 m-male group by 33%. Compared with SHR-6m-female group, mRNA levels of TNFa in the kidney of SHR-6m-male group increased by 54%, Compared with SHR-12m-female group, mRNA levels of TNFa in the kidney of SHR-12m-male group increased by 50%. The mRNA levels of TNFa in the kidney of same age SHR(6m,12m)did not change significantly.
3. Gender differences in development of renovascular hypertension
10-week-old SD rats were prepared by the narrow side of the renal artery to development renovascular hypertension(2K1C). After removal of both ovaries of a group of female rats(VOX),2K1C operation was performed in the same female rats. After 6 months of regular feeding, rats were instrumented to determine blood pressure(BP) in anesthesia state. After BP recording, a polyethy cannula(PE-50) was inserted into the carotid artery to collecting blood for determination of AngⅡ, ET-1 and inflammatory cytokines by using ELISA kit. Rats were killed and the thoracic aorta, heart, kidney were collected and frozen. Observation of target organ damage. Western Blot method was applicated to detect the protein expression of ACE, ACE2, AT1 and AT2 in the thoracic aorta, heart and kidney tissue. The main findings of this study are as following:
3.1 Hemodynamic parameter in 2K1C rats
Compared with 2K1C-sham-male rats, SBP.DBP were significantly increased in all 2K1C rats, and HP was significantly lower in 2K1C-female rats. SBP、DBP were significantly higher in 2K1C-female rats and similar in 2K1C-OVX rats when compared with 2K1C-male rats.
3.2 EOD parameter in 2K1C rats
VW/BW, LVW/BW, LVW/BW and RKW/BW were significantly higher in 2K1C rats. VW/BW, LVW/BW, LVW/BW and RKW/BW were significantly higher in 2K1C-female rats when compared with 2K1C-male rats and 2K1C-OVX rats. Compared with 2K1C-sham-male rats, AW/length were significantly higher in 2K1C-male, and was similar in 2K1C-OVX rats and 2K1C-female rats.
3.3 plasma AngⅡ, ET-1 and serum inflammatory factors in 2K1C rats
Compared with 2K1C-sham-male rats, plasma AngⅡwere significantly higher in 2K1C-male, and similar in 2K1C-OVX rats and 2K1C-female rats, plasma ET-1 were significantly higher in all 2K1C rats.plasma ET-1 were significantly higher in 2K1C-female rats when compared with 2K1C-male rats and 2K1C-OVX rats. Compared with 2K1C-sham-male rats, serum IL-1βwere significantly higher in 2K1C-OVX rats and were significantly lower in 2K1C-female rats, serum IL-6 were significantly lower in 2K1C-OVX rats and another groups did not change. Compared with 2K1C-sham-male rats, serum TNF-a were significantly higher in all 2K1C rats.
3.4 Protein levels of ACE, ACE2, AT1 and AT2 in 2K1C rats
Thoracic aorta tissue:the protein levels of ACE were significantly higher in 2K1C-female rats and 2K1C-male rats, were similar in 2K1C-OVX rats when compared with 2K1C-sham-male rats.the protein levels of ACE were significantly higher in 2K1C-female rats when compared with 2KIC-male rats. The protein levels of ACE2 were significantly higher in 2K1C-OVX rats and in 2K1C-female rats, on change in 2K1C-male rats when compared with 2K1C-male rats. The protein levels of AT1 receptor were on significantly change in all 2K1C rats when compared with 2K1C-sham-male rats. Compared with 2KlC-male rats, the protein levels of AT1 receptor were significantly lower in 2K1C-OVX rats and in 2K1C-female rats. Compared with 2K1C-sham-male rats the protein levels of AT2 receptor were significantly higher in all 2K1C rats.
Kidney tissue:Compared with 2K1C-sham-male rats, the protein levels of ACE were significantly higher in 2K1C-female rats, the protein levels of ACE2 were no significantly change in all 2K1C rats, the protein levels of AT1 receptor were significantly lower in 2K1C-female rats, and the protein levels of AT2 receptor were also significantly lower in 2K1C-female rats.
Heart tissue:Compared with 2K1C-sham-male rats, the protein levels of ACE were significantly higher in 2K1C-female rats, the protein levels of ACE2 were significantly lower in 2K1C-female rats and in 2K1C-male rats, the protein levels of AT1 receptor were significantly higher in 2K1C-female rats and in 2K1C-male rats. Compared with 2K1C-male rats, AT1 receptor were significantly higher in 2K1C-female rats. Compared with 2K1C-sham-male rats, the protein levels of AT2 receptor were significantly lower in 2K1C-OVX rats.
Conclusions:
1 Gene expression of all the components of RAS, including ACE2 and AT2 receptor in the heart and the aorta, was increased in SHR when compared with WKY rats; Hypertensive cardiovascular hypertrophy was significantly related to mRNA expression of local RAS and inflammatory factors, but not to plasma AngⅡin SHR; Stepwise multiple-regression analysis showed that left ventricular hypertrophy was mainly determined by increased DBP and cardiac ACE gene expression; and aortic hypertrophy was mainly correlated with decreased baroreflex sensitivity.
2. Effects of estrogen on the adult(6 months)blood pressure in spontaneously hypertensive rats and target organ damage have a certain effect of mitigation; the plasma concentrations of AngⅡwas significantly higher in the male SHR, the plasma concentrations of ET-1 was significantly lower in the male SHR. Female adult spontaneously hypertensive rats serum concentrations of IL-6 and renal tissue mRNA expression was significantly lower than the male same age group, and increased with age; the serum concentrations of TNFa in the elderly female groups was significantly lower than the male same age group, the TNFa mRNA expression levels of female adult and elderly groups in spontaneously hypertensive rat was significantly lower than the male same age group. The serum concentrations of IL-1β，IL-6 and estradiol was significantly related to the plasma concentrations of Ang II.
3.10-week-old SD rats were prepared by the narrow side of the renal artery to development renovascular hypertension(2K1C). After removal of both ovaries of a group of female rats(VOX)to development low levels of estrogen,2K1C operation was performed in one group female rats. Compared with 2K1C-sham-male rats, SBP、DBP were significantly higher in all 2K1C rats. SBP、DBP were significantly higher in 2K1C-female rats and similar in 2K1C-OVX rats when compared with 2K1C-male rats. It is likely that the effect of estrogen on renovascular hypertension was depending on promoting promote the role of AngⅡby increasing the release of ET-1, increasing the protein expression levels of ACE in heart, thoracic aorta and kidney tissue, and increasing the protein expression level of AT1 receptors in heart tissue.
在高血压病的发生发展过程中,严重的器官损伤可导致致命性的并发症。因此,逆转或减少靶器官损伤,防止并发症的发生是非常必要的。肾素血管紧张素系统和炎症在高血压靶器官损伤中可能扮演着重要的角色。女性激素可影响血压水平,对心血管系统具有一定的保护作用。本课题旨在研究性别对高血压局部RAS与炎症因子作用的影响。
方法与结果：
1.局部RAS、炎症与自发性高血压大鼠器官损伤
应用清醒自由活动大鼠血流动力学测定系统对WKY和SHR大鼠的血压、血压波动性进行监测,随后应用RT-PCR技术对局部组织中的TNF-α、IL-1β、IL-6及renin、ACE、ACE2、AT1、AT2进行检测,研究SHR心脏和主动脉中RAS各组分的基因表达；局部组织RAS的各种组分的基因表达与心血管肥大之间的关系；局部炎症因子对血管肥大的作用,以及其与局部RAS成分之间的关系。
1.1血流动力学变化、血浆AngⅡ的浓度、血清炎症因子的浓度及器官损伤
与WKY大鼠相比,在SHR中SBP、DBP及BPV明显增高,HP、HPV及BRS明显降低;血浆中AngⅡ的含量明显增高,血清IL-1β、IL-6的含量明显增高,SHR大鼠的器官损伤特点比较明显,主要表现在LVW/BW和AW/length明显增加。
1.2 RAS、炎症因子的mRNA在SHR心脏和主动脉中的表达
与WKY大鼠相比,SHR心脏中血管紧张素原、肾素、ACE2、AT1和AT2的mRNA表达分别增加了314%、212%、119%、215%和250%；WKY和SHR在心脏中ACE mRNA的表达无显著差异;SHR主动脉中ACE、ACE2、AT1和AT2的mRNA表达分别增加了116%、86%、107%和110%,WKY和SHR主动脉中血管紧张素原和肾素的mRNA表达无显著差异。
与WKY大鼠相比,SHR心脏中TNF-α、IL-1β和IL-6的mRNA表达分别增加了213%、132%和91%；与WKY大鼠相比,SHR主动脉中TNF-α和IL-6的mRNA表达分别增加了220%和458%,WKY和SHR主动脉中IL-1β的mRNA表达无显著差异。
1.3 SHR血浆中AngⅡ浓度和血流动力学参数与心脏和主动脉血管肥大的关系
BP和BPV与LVW/BW和AW/length之间呈显著正相关；而BRS与心血管肥大呈显著负相关。SHR血浆中AngⅡ浓度与LVW/BW和AW/length无显著相关。
1.4 SHR局部组织的RAS和炎症因子mRNA的表达与心脏血管肥大的关系
SHR心脏中ACE、ACE2和TNF-α的mRNA表达与LVW/BW之间呈显著正相关；而在主动脉中,血管紧张素原、ACE2、TNF-α、IL-6和IL-1β的mRNA表达与AW/length之间呈显著正相关。
1.5 SHR局部组织中RAS的mRNA表达与炎症因子mRNA表达之间的关系
SHR心脏中TNF-a的mRNA与肾素、AT1和AT2的mRNA表达之间呈显著正相关；主动脉中ACE2和AT2的mRNA表达与TNF-a的mRNA表达之间呈显著正相关。
SHR心脏中血管紧张素原、肾素、ACE、ACE2和AT2的mRNA表达与IL-6的mRNA表达之间呈显著正相关；主动脉中血管紧张素原、肾素、ACE2、AT1和AT2的mRNA表达与IL-6的mRNA表达之间呈显著正相关。
1.6多元逐步回归分析
DBP在LW/BW中的β=0.493,P<0.01,ACE基因表达的p=0.449,P<0.01。AW/length与BRS独立相关,β=-0.810,P<0.01。决定心血管损伤的平均共系数是0.596。这表明血流动力学因子、DBP、BRS以及ACE mRNA在高血压诱导的心血管肥大占59.6%的变异。
2.性别对自发性高血压大鼠炎症反应的作用研究
采用6月龄和12月龄的SHR,用无创尾动脉测压系统测定血压；麻醉后颈动脉插管取血样本,随后取器官样本,用放免法测定血浆AngⅡ、ET-1浓度,血清E2、TNF-α、IL-6和IL-1β浓度；大体观察靶器官损伤；应用RT-PCR技术检测肾脏组织中的TNF-α、IL-1β、IL-6的mRNA。
2.1性别对SHR的收缩压及靶器官损伤的影响
雄性SHR的SBP和体重明显高于同龄的雌性SHR,同性别的SHR随着年龄的增加,SBP和体重明显增加。同龄雌性SHR的VW/BW、LVW/BW和RVW/BW明显大于雄性组；同性别的雌性SHR随着年龄的增加,心室指数增大,同性别的雄性SHR随着年龄的增加,右心室指数增大。雄性SHR的LVW/RVW比值明显大于雌性,同性别的SHR随着年龄的增加,LVW/RVW增加。雄性SHRAW/length明显大于同龄雌性；同性别的SHR随着年龄的增加,AW/length增大。肾指数RKW/BW的性别二重性仅存在于12mSHR中,随着随着年龄的增加肾脏损伤加重。
2.2 SHR的AngⅡ、ET、E2及炎症因子的性别差异
在同龄异性SHR中,雄性组血浆AngⅡ的含量明显大于雌性组；雌性组血浆ET-1的量明显大于雄性组；均无年龄因素的影响。血清IL-1p：SHR-6m组明显高于同龄雄性组,雄性SHR-12m组明显高于同龄雌性组,SHR-12m组明显高于SHR-6m组。血清IL-6：雄性SHR组明显高于同龄的雌性组,SHR-12m组明显高于SHR-6m组。血清TNFα:SHR-6m不存在性别差异,雄性SHR-12m组明显高于同龄的雌性组；SHR-12m组明显高于SHR-6m组。
2.36月龄SHR的AngⅡ、ET与E2及炎症因子的相关性
SHR血浆AngⅡ与血清炎症因子IL-1p及IL-6之间呈正相关,而与TNF-α之间没有相关性；ET与各炎症因子之间没有相关性。雌性SHR血浆AngⅡ与血清E2之间呈正相关。
2.4 SHR肾组织中炎症因子mRNA表达
肾组织中IL-6 mRNA的表达：雌性SHR-6m组明显低于同龄雄性组(6m:53%,12m：272%)SHR-12m组明显高于同性别SHR-6m组(雌性：69%,雄性：242%)。IL-1p的mRNA的表达：SHR-12m组高于同性别SHR-6m组(雌性：25%,雄性：33%)。TNFa的mRNA的表达：雌性SHR-6m和SHR-12m明显低于同龄雄性(6m：54%,12m：50%),无年龄因素的影响。
3.性别对肾血管性高血压大鼠发生发展的影响
采用10周龄SD大鼠钳夹一侧肾动脉血管制备肾血管性高血压(2K1C),摘除一组雌性大鼠双侧卵巢(VOX)造成雌激素水平低下,再钳夹一侧肾动血管脉制备肾血管性高血压。常规饲养6个月,麻醉下股动脉插管测血压后,取血及器官。用ELISA法测定各组大鼠血浆中AngⅡ和ET-1的浓度,血清中炎症因子的浓度。观察靶器官损伤。应用Western Blot方法,检测各组大鼠胸主动脉、心脏和肾脏的组织中ACE、ACE2、AT1和AT2蛋白质表达。
3.12K1C大鼠血流动力学参数的测定
与2K1C-sham-雄性组比较,各2K1C手术组SBP、DBP显著性增高,而HP在2K1C-雌性组显著性降低,与2K1C-雄性组比较,2K1C-雌性组SBP、DBP显著性增高,2K1C-OVX组无差别,两组数据基本接近；与2K1C-雌性组比较,2K1C-OVX组SBP、DBP明显降低。
3.22K1C大鼠靶器官的测定
与2K1C-sham-雄性组比较,,VW/BW、LVW/BW、LVW/BW和RKW/BW均显著性增加；2K1C-雌性组的各项指标均明显高于2K1C-雄性组和2K1C-OVX组；AW/length仅在2K1C-雄性组显著升高,而在其他各组则无变化。
3.32K1C大鼠血浆AngII、ET-1和血清炎症因子浓度的测定
血浆AngⅡ:仅在2K1C-雄性组明显升高,而在其他各组均无差异。血浆ET-1：2K1C手术各组明显高于假手术组,并且2K1C-雌性组明显高于2K1C-雄性组和2K1C-OVX组。血清IL-1β:2K1C-OVX组升高,而2K1C-雌性组则是下降,其下降程度与2K1C-雄性组相比有显著性差异。血清IL-6：2K1C-OVX组减少,其他各组均无显著性变化；与2K1C-雌性组比较,2K1C-OVX组血清IL-6的浓度也明显减少。血清TNF-α:2K1C手术组明显升高；2K1C-OVX组升高作用最为明显。
3.4 2K1C大鼠组织中RAS蛋白表达的测定
血管组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE的蛋白表达2K1C-雄性组和2K1C-雌性组明显升高,2K1C-OVX组无变化,与2K1C-雄性组比较,2K1C-雌性组明显升高；ACE2蛋白表达2K1C-OVX组和2K1C-雌性组明显升高,2K1C-雄性组无变化；与2K1C-sham-雄性组比较,AT1受体的蛋白表达无差异,与2K1C-雄性组比较,2K1C-雌性组和2K1C-OVX组明显减少；AT2受体的蛋白表达各手术组明显增加,2K1C-雌性组增加最为明显。肾脏组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE蛋白的表达2K1C-雌性组明显升高；ACE2蛋白的表达各组间无统计学差异；AT1受体的蛋白表达2K1C-雌性组明显减少;AT2受体的蛋白表达2K1C-雄性组和2K1C-OVX组无统计学差异,2K1C-雌性组明显减少。心脏组织RAS蛋白表达：与2K1C-sham-雄性组比较,ACE蛋白的表达2K1C-雌性组升高；ACE2蛋白的表达2K1C-雄性组和2K1C-雌性组明显下降,两组间无差异；AT1受体的蛋白表达2K1C-雄性组和2K1C-雌性组增加,2K1C-雌性组与其他各组相比,AT1受体的蛋白表达明显增加。AT2受体的蛋白表2K1C-OVX组降低。
结论：
1.与血压正常的对照组比较,自发性高血压大鼠组的心脏和主动脉中RAS所有组分和炎性细胞因子的基因表达增加；左心室肥厚与心脏局部RAS的ACE和ACE2基因,TNF-α基因表达正相关相关；主动脉肥厚与主动脉局部RAS血管紧张素和ACE2基因,炎性细胞因子TNF-α、IL-1β和IL-6的基因表达呈正相关。ACE2和AT2在RAS中可能并没有起主要作用,但可部分对抗ACE和AT1在高血压靶器官损伤的作用。
2.雌激素对成年(6月龄)自发性高血压大鼠的血压水平和靶器官的损伤有一定的缓解作用；雌性成年组自发性高血压大鼠血浆AngⅡ明显低于同龄雄性组,ET-1明显高于同龄雄性组；血清中IL-6的浓度和肾组织中的mRNA表达显著低于同龄雄性组,并随着年龄的增长而增加；雌性老年组血清TNF-α的浓度,雌性成年组和老年组自发性高血压大鼠肾组织中TNF-αmRNA表达水平明显低于同龄雄性组；线性回归分析表明,IL-1β和IL-6均与AngⅡ呈显著正相关；雌二醇与AngⅡ呈显著正相关。
3)SD大鼠一侧肾动脉血管钳夹后,形成肾血管性高血压(2K1C)。2K1C雌性大鼠血压水平,心肌肥厚和肾脏损伤程度比2K1C雄性大鼠严重；双侧卵巢切除导致雌激素水平低下后,再钳夹一侧肾动脉血管,肾血管性高血压形成得严重程度轻与雌性大鼠,血压水平接近雄性大鼠；雌性2K1C大鼠肾血管性高血压严重程度的机制可能与促进ET-1的释放,明显升高心脏、胸主动脉和肾脏组织中ACE的蛋白表达,明显升高心脏组织中AT1受体的蛋白表达,而促进AngⅡ的作用有关。
Objective:
The development of hypertensive end organ damage(EOD)plays a pivotal role in the occurrence of hypertensive complications. It is therefore essential to reverse, reduce or prevent EOD from happening in the treatment of hypertension. Renin-angiotensin system may also play an important role in hypertensive EOD. Recently, an emerging concept contends that inflammation plays a predominant role in the progression of hypertension and is also involved in the triggering of hypertension-associated cardiovascular complications. Female sex hormones have the ability to affect blood pressure levels. Accumulating evidence from experimental studies showed that estrogens have a cardioprotective influence in women by improving endothelial function, and regulating the response to inflammation. Therefore, the present studyies were designed three parts to evealuatd the influence of estrogens on local renin-angiotensin system and inflammatory factors in hypertensive rats.
Methods and Results:
1. Local RAS and inflammatory factors are involved in cardiovascular hypertrophy in spontaneously hypertensive rats
SHR and WKY rats were used in this study. The blood pressure and baroreflex sensitivity were measured in conscious state. After hemodynamic monitoring and BRS studies, the animal was weighed, anesthetized, and killed by decapitation. The aorta and heart were immediately excised and rinsed in cold physiological saline for histopath-ological examination. The mRNA levels of angiotensinogen, renin, ACE, ACE2, AT1, AT2 in local tissue were determined using quantitative real-time polym-erase chain reaction. The plasma was collected for the determination of angiotensin II concentration using the radioimmunoassay kit. The main findings of this study are as following:
1.1 Hemodynamic parameter, plasma AngⅡ, serum inflammatory factors and EOD in SHR
Compared with WKY rats, BP, BPV, plasma AngⅡconcentration, serum IL-1βand IL-6 concentration were significantly higher, while HP, HPV and BRS were significantly lower in SHR. SHR present with obvious cardiovascular hypertrophy characterized by increased LVW/BW and AW/length.
1.2 mRNA expression of RAS and inflammatory factors in the heart and aorta of SHR
Compared with WKY rats, mRNA levels of angiotensinogen, renin, ACE2, AT1 and AT2 in the heart of SHR increased by 314%,212%,119%,215% and 250% respectively. There was no difference in ACE mRNA in the heart between SHR and WKY rats. mRNA levels of ACE, ACE2, AT1 and AT2 in the aorta of SHR increased by 116%,86%, 107% and 110% respectively when compared with those of WKY rats. There was no significant difference in angiotensinogen and renin mRNA in the aorta between SHR and WKY rats.
In addition, mRNA levels of TNFα, IL-1βand IL-6 in the heart of SHR increased by 213%,132% and 91% respectively, and mRNA levels of TNFa and IL-6 in the aorta of SHR increased by 220% and 458% respectively, when compared with WKY rats. There was no significant difference in IL-1βmRNA in the aorta between SHR and WKY rats.
1.3 Correlations between hemodynamics, plasma AngⅡconcentration, serum inflammatory factors and cardiovascular hypertrophy in SHR
BP and BPV were found to be positively correlated with LVW/BW and AW/length, while BRS was negatively correlated with cardiovascular hypertrophy. Plasma AngⅡwas insignificantly correlated with any cardiovascular damage parameter.
1.4 Correlations between local mRNA expression of RAS and inflammatory factors and cardiovascular damage in SHR
ACE, ACE2 and TNF-αmRNA expression in the heart was positively correlated with LVW/BW, while renin, ACE2, TNF-α, IL-1βand IL-6 mRNA expression in the aorta was also positively concerned with AW/length.
1.5 Relationships between local tissue RAS mRNA and inflammatory factor mRNA in SHR
Renin, AT1 and AT2 mRNA expression in the heart was positively correlated with TNF-αmRNA. ACE2 and AT2 mRNA expression in the aorta was also positively correlated with TNF-αmRNA.
Angiotensinogen, renin, ACE, ACE2 and AT2 mRNA expression in the heart was positively correlated with IL-6 mRNA. Angiotensinogen, renin, ACE2, AT1 and AT2 mRNA expression in the aorta was positively correlated with IL-6 mRNA
1.6 Stepwise multivariate regression analysis
The regression equations indicated that LV weight/BW was independently correlated with DBP(β=0.493, P< 0.01; whereβis the standardized partial regressive coefficient)and ACE gene expression(β=0.449, P<0.01). Aortic weight/length was independently correlated with BRS(β=-0.810, P<0.01). The determinant coefficient (R2) for cardiovascular damage averaged 0.596. This value means that the independent hemodynamic factors, DBP, BRS and ACE mRNA expression level explain 59.6% of the variation in the hypertensive cardiovascular hypertrophy.
2. Gender related influence on inflammatory factors in spontaneously hypertensive rats
Both male and female SHR rats were used in this study. The blood pressure was measured in conscious state by using the tail-cuff plethysmography method. The rats was anesthetized, and a polyether cannula (PE-50) was inserted into the carotid artery to collecting blood sample, the kidneys were collected and immediately frozen in liquid nitrogen. The aorta and heart were immediately excised and rinsed in cold physiological saline for histopathological examination. The mRNA levels of TNF-a, IL-1βand IL-6 in local tissue were determined using quantitative real-time polymerase chain reaction. The plasma was determined of angiotensinⅡ, ET-1 concentration, the serum of TNF-a, IL-1βand IL-6 concentration was determined by using the radioimmunoassay kit. The main finding of this study are as following:
2.1 Hemodynamic parameter, plasma AngⅡ, serum inflammatory factors and EOD in SHR
Compared with SHR-12m group, SBP and body weight(BW)were no change in SHR-6m group. SBP, BW, LVW/RVW and AW/length were significantly higher in the same age male SHR when compared with female SHR, and VW/BW, LVW/BW, RVW/BW were significantly lower in the same age male SHR. Compared with SHR-6m-female, VW/BW, LVW/RVW, RKW/BW and AW/length were significantly higher in the SHR-12m-female group. Compared with SHR-6m-male group, RVW/BW, LVW/RVW, RKW/BW and AW/length were significantly higher in the SHR-12m-male group.
2.2 plasma Ang II, ET-1 and serum inflammatory factors in SHR
Compared with female SHR, plasma AngⅡwas significantly higher in the male SHR, plasma ET-1 was significantly lower in the male SHR. The serum IL-1βwas significantly higher in the SHR-6m-female group than those of SHR-6m-male group, compared with SHR-12m-male group, serum IL-1βwas significantly lower in the SHR-12m-female group. Compared with SHR-male, serum IL-6 was significantly higher in the same age SHR-female, compared with SHR-6m group, serum IL-6 was significantly higher in the same sex SHR-12m group. serum TNF-αwas no significantly change in the SHR-6m group, compared with SHR-12m-male group, serum TNF-a was significantly lower in the SHR-12m-female group.
2.3 Correlations between plasma AngⅡ, ET-1 and serum inflammatory factors in SHR
Plasma Ang II was found to be positively correlated with serum IL-1βand IL-6. Plasma Ang II was positively correlated with serum E2. Plasma ET-1 was not any correlated with serum inflammatory factors in SHR.
2.4 mRNA expression of inflammatory factors in the kidney of SHR
group Compared with SHR-6m-female group, mRNA levels of IL-6 in the kidney of SHR-6m-male group increased by 53%, Compared with SHR-12m-female group, mRNA levels of IL-6 in the kidney of SHR-12m-male group increased by 272%. Compared with SHR-6m-male group, mRNA levels of IL-1βin the kidney of SHR-12 m-male group by 33%. Compared with SHR-6m-female group, mRNA levels of TNFa in the kidney of SHR-6m-male group increased by 54%, Compared with SHR-12m-female group, mRNA levels of TNFa in the kidney of SHR-12m-male group increased by 50%. The mRNA levels of TNFa in the kidney of same age SHR(6m,12m)did not change significantly.
3. Gender differences in development of renovascular hypertension
10-week-old SD rats were prepared by the narrow side of the renal artery to development renovascular hypertension(2K1C). After removal of both ovaries of a group of female rats(VOX),2K1C operation was performed in the same female rats. After 6 months of regular feeding, rats were instrumented to determine blood pressure(BP) in anesthesia state. After BP recording, a polyethy cannula(PE-50) was inserted into the carotid artery to collecting blood for determination of AngⅡ, ET-1 and inflammatory cytokines by using ELISA kit. Rats were killed and the thoracic aorta, heart, kidney were collected and frozen. Observation of target organ damage. Western Blot method was applicated to detect the protein expression of ACE, ACE2, AT1 and AT2 in the thoracic aorta, heart and kidney tissue. The main findings of this study are as following:
3.1 Hemodynamic parameter in 2K1C rats
Compared with 2K1C-sham-male rats, SBP.DBP were significantly increased in all 2K1C rats, and HP was significantly lower in 2K1C-female rats. SBP、DBP were significantly higher in 2K1C-female rats and similar in 2K1C-OVX rats when compared with 2K1C-male rats.
3.2 EOD parameter in 2K1C rats
VW/BW, LVW/BW, LVW/BW and RKW/BW were significantly higher in 2K1C rats. VW/BW, LVW/BW, LVW/BW and RKW/BW were significantly higher in 2K1C-female rats when compared with 2K1C-male rats and 2K1C-OVX rats. Compared with 2K1C-sham-male rats, AW/length were significantly higher in 2K1C-male, and was similar in 2K1C-OVX rats and 2K1C-female rats.
3.3 plasma AngⅡ, ET-1 and serum inflammatory factors in 2K1C rats
Compared with 2K1C-sham-male rats, plasma AngⅡwere significantly higher in 2K1C-male, and similar in 2K1C-OVX rats and 2K1C-female rats, plasma ET-1 were significantly higher in all 2K1C rats.plasma ET-1 were significantly higher in 2K1C-female rats when compared with 2K1C-male rats and 2K1C-OVX rats. Compared with 2K1C-sham-male rats, serum IL-1βwere significantly higher in 2K1C-OVX rats and were significantly lower in 2K1C-female rats, serum IL-6 were significantly lower in 2K1C-OVX rats and another groups did not change. Compared with 2K1C-sham-male rats, serum TNF-a were significantly higher in all 2K1C rats.
3.4 Protein levels of ACE, ACE2, AT1 and AT2 in 2K1C rats
Thoracic aorta tissue:the protein levels of ACE were significantly higher in 2K1C-female rats and 2K1C-male rats, were similar in 2K1C-OVX rats when compared with 2K1C-sham-male rats.the protein levels of ACE were significantly higher in 2K1C-female rats when compared with 2KIC-male rats. The protein levels of ACE2 were significantly higher in 2K1C-OVX rats and in 2K1C-female rats, on change in 2K1C-male rats when compared with 2K1C-male rats. The protein levels of AT1 receptor were on significantly change in all 2K1C rats when compared with 2K1C-sham-male rats. Compared with 2KlC-male rats, the protein levels of AT1 receptor were significantly lower in 2K1C-OVX rats and in 2K1C-female rats. Compared with 2K1C-sham-male rats the protein levels of AT2 receptor were significantly higher in all 2K1C rats.
Kidney tissue:Compared with 2K1C-sham-male rats, the protein levels of ACE were significantly higher in 2K1C-female rats, the protein levels of ACE2 were no significantly change in all 2K1C rats, the protein levels of AT1 receptor were significantly lower in 2K1C-female rats, and the protein levels of AT2 receptor were also significantly lower in 2K1C-female rats.
Heart tissue:Compared with 2K1C-sham-male rats, the protein levels of ACE were significantly higher in 2K1C-female rats, the protein levels of ACE2 were significantly lower in 2K1C-female rats and in 2K1C-male rats, the protein levels of AT1 receptor were significantly higher in 2K1C-female rats and in 2K1C-male rats. Compared with 2K1C-male rats, AT1 receptor were significantly higher in 2K1C-female rats. Compared with 2K1C-sham-male rats, the protein levels of AT2 receptor were significantly lower in 2K1C-OVX rats.
Conclusions:
1 Gene expression of all the components of RAS, including ACE2 and AT2 receptor in the heart and the aorta, was increased in SHR when compared with WKY rats; Hypertensive cardiovascular hypertrophy was significantly related to mRNA expression of local RAS and inflammatory factors, but not to plasma AngⅡin SHR; Stepwise multiple-regression analysis showed that left ventricular hypertrophy was mainly determined by increased DBP and cardiac ACE gene expression; and aortic hypertrophy was mainly correlated with decreased baroreflex sensitivity.
2. Effects of estrogen on the adult(6 months)blood pressure in spontaneously hypertensive rats and target organ damage have a certain effect of mitigation; the plasma concentrations of AngⅡwas significantly higher in the male SHR, the plasma concentrations of ET-1 was significantly lower in the male SHR. Female adult spontaneously hypertensive rats serum concentrations of IL-6 and renal tissue mRNA expression was significantly lower than the male same age group, and increased with age; the serum concentrations of TNFa in the elderly female groups was significantly lower than the male same age group, the TNFa mRNA expression levels of female adult and elderly groups in spontaneously hypertensive rat was significantly lower than the male same age group. The serum concentrations of IL-1β，IL-6 and estradiol was significantly related to the plasma concentrations of Ang II.
3.10-week-old SD rats were prepared by the narrow side of the renal artery to development renovascular hypertension(2K1C). After removal of both ovaries of a group of female rats(VOX)to development low levels of estrogen,2K1C operation was performed in one group female rats. Compared with 2K1C-sham-male rats, SBP、DBP were significantly higher in all 2K1C rats. SBP、DBP were significantly higher in 2K1C-female rats and similar in 2K1C-OVX rats when compared with 2K1C-male rats. It is likely that the effect of estrogen on renovascular hypertension was depending on promoting promote the role of AngⅡby increasing the release of ET-1, increasing the protein expression levels of ACE in heart, thoracic aorta and kidney tissue, and increasing the protein expression level of AT1 receptors in heart tissue.
引文
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