Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells

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• 作者：Shrinidh Joshi^a ; Narayanaganesh Balasubramanian^b ; Goutham Vasam^a ; ^b ; Yagna PR Jarajapu^a ; ^{Yagna.Jarajapu@ndsu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACE ; ACE2 ; MLN-4760 ; DX600 ; CD34+ cells ; Lineage-depleted cells
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 March 2016
• 年：2016
• 卷：774
• 期：Complete
• 页码：25-33
• 全文大小：667 K

文摘

Angiotensin-converting enzymes, ACE and ACE2, are key members of renin angiotensin system. Activation of ACE2/Ang-(1-7) pathway enhances cardiovascular protective functions of bone marrow-derived stem/progenitor cells. The current study evaluated the selectivity of ACE2 inhibitors, MLN-4760 and DX-600, and ACE and ACE2 activities in human (hu) and murine (mu) bone marrow cells. Assays were carried out in hu and mu mononuclear cells (MNCs) and huCD34⁺ cells or mu-lineage-depleted (muLin^-) cells, human-recombinant (rh) enzymes, and mu-heart with enzyme-specific substrates. ACE or ACE2 inhibition by racemic MLN-4760, its isomers MLN-4760-A and MLN-4760-B, DX600 and captopril were characterized. MLN-4760-B is relatively less efficacious and less-selective than the racemate or MLN-4760-A at hu–rhACE2, and all three of them inhibited 43% rhACE. In huMNCs, MLN-4760-B detected 63% ACE2 with 28-fold selectivity over ACE. In huCD34⁺ cells, MLN-4760-B detected 38% of ACE2 activity with 63-fold selectivity. In mu-heart and muMNCs, isomer B was 100- and 228-fold selective for ACE2, respectively. In muLin^- cells, MLN-4760-B detected 25% ACE2 activity with a pIC₅₀ of 6.3. The racemic mixture and MLN-4760-A showed lower efficacy and poor selectivity for ACE2 in MNCs and mu-heart. ACE activity detected by captopril was 32% and 19%, respectively, in huCD34⁺ and muLin^- cells. DX600 was less efficacious, and more selective for ACE2 compared to MLN-4760-B in all samples tested. These results suggest that MLN-4760-B is a better antagonist of ACE2 than DX600 at 10 µm concentration in human and murine bone marrow cells, and that these cells express more functional ACE2 than ACE.