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

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Renal Physiology

Background:

• Angiotensin-(1-12) [Ang-(1-12)] is recognized as a precursor to Angiotensin II (Ang II), a key mediator of cardiac activity.
• The direct impact of Ang-(1-12) on cardiomyocyte contractility and intracellular calcium ([Ca2+]i) regulation in both normal and heart failure (HF) states remains incompletely understood.

Purpose of the Study:

• To investigate the direct contractile effects of Ang-(1-12) on cardiomyocytes from normal and HF rat models.
• To elucidate the role of Ang-(1-12) in modulating intracellular calcium ([Ca2+]i) handling and contractility in the context of cardiac health and disease.

Main Methods:

• Comparison of left ventricle (LV) myocyte contractile and calcium transient ([Ca2+]iT) responses to Ang II and Ang-(1-12) in normal rats and rats with isoproterenol-induced HF.
• Assessment of the effects of chymostatin, Rp-cAMPS (cAMP analog), and pertussis toxin (PTX) on Ang-(1-12) and Ang II-mediated myocyte function.

Main Results:

• Ang-(1-12) significantly increased cardiomyocyte contractility (dL/dtmax) and [Ca2+]iT in normal rat myocytes, comparable to Ang II.
• In HF myocytes, Ang-(1-12) and Ang II exhibited attenuated positive inotropic effects, with reduced increases in dL/dtmax and [Ca2+]iT.
• Chymostatin abolished Ang-(1-12)-induced effects, while Rp-cAMPS prevented them in both normal and HF myocytes. PTX augmented Ang II effects in HF myocytes.

Conclusions:

• Ang-(1-12) directly stimulates cardiomyocyte contractile function and [Ca2+]iT in normal and HF rats via a chymase-dependent mechanism.
• The altered inotropic responses to Ang-(1-12) and Ang II in HF are mediated by a cAMP-dependent pathway involving both stimulatory G proteins and inhibitory PTX-sensitive G proteins.