Critical role of the chymase/angiotensin-(1-12) axis in modulating cardiomyocyte contractility

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:264

Article

Li, Tiankai^1,2  Zhang, Xiaowei^2,3  Cheng, Heng-Jie^1,2  Zhang, Zhi^2,4  Ahmad, Sarfaraz^5,6,7,8  Varagic, Jasmina^5,6,7,8  Li, Weimin¹  Cheng, Che Ping^1,2  Ferrario, Carlos M.^5,6,7,8 

[1] Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin, Heilongjiang, Peoples R China

[2] Wake Forest Sch Med, Dept Internal Med, Sect Cardiovasc Med, Winston Salem, NC USA

[3] Nantong Univ, Affiliated Hosp 2, Dept Cardiol, Nantong, Peoples R China

[4] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Cardiovasc Dept, Shanghai, Peoples R China

[5] Wake Forest Sch Med, Dept Surg, Winston Salem, NC USA

[6] Wake Forest Sch Med, Dept Internal Med Nephrol, Winston Salem, NC USA

[7] Wake Forest Sch Med, Dept Physiol, Winston Salem, NC USA

[8] Wake Forest Sch Med, Dept Pharmacol, Winston Salem, NC USA

关键词: Angiotensin-(1-12);    Chymase;    Heart failure;    Cardiomyocyte;    Contractility;    Calcium transient;   

DOI  :  10.1016/j.ijcard.2018.03.066

来源: Elsevier

【 摘 要 】

Background: Angiotensin-(1-12) [Ang-(1-12)] is a chymase-dependent source for angiotensin II (Ang II) cardiac activity. The direct contractile effects of Ang-(1-12) in normal and heart failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1-12) may modulate [Ca2+](i) regulation and alter cardiomyocyte contractility in normal and HF rats. Methods and results: We compared left ventricle (LV) myocyte contractile and calcium transient ([Ca2+](iT)) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and 16 age-matched controls. In normal myocytes, versus baseline, Ang II (10(-6) M) superfusion significantly increased myocyte contractility (dL/dt(max): 40%) and [Ca2+](iT) (29%). Ang-(1-12) (4 x 10(-6) M) caused similar increases in dL/dt(max) (34%) and [Ca2+](iT) (25%). Compared with normal myocytes, superfusion of Ang II and Ang-(1-12) in myocytes obtained from rats with isoproterenol-induced HF caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dt(max) and [Ca2+](iT). Chymostatin abolished Ang-(1-12)-mediated effects in normal and HF myocytes. The presence of an inhibitory cAMP analog, Rp-cAMPS prevented Ang-(1-12)-induced inotropic effects in both normal and HF myocytes. Incubation of HF myocytes with pertussis toxin (PTX) further augmented Ang II-mediated contractility. Conclusions: Ang-(1-12) stimulates cardiomyocyte contractile function and [Ca2+](iT) in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes are mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins. (C) 2018 Elsevier B.V. All rights reserved.

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