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

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.