Surviving Infarction One Gene at a Time
Decreased Remodeling and Mortality in Engineered Mice Lacking the Angiotensin II Type 1A Receptor
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Angiotensin II (Ang II), named for its first-discovered physiological role as a potent vasoconstrictor, is perhaps the most widely studied paradigm of a pleiotropic agent in cardiovascular biology and medicine, with diverse targets and effects far beyond those first envisioned.1 Notably, Ang II has received scrutiny as an intramyocardial growth factor (one, among others) that is produced locally within the myocardium, is released from cardiac cells after mechanical load, and is subsequently expressed at higher levels as part of the “hypertrophic phenotype.”2 Both cardiac myocytes and fibroblasts are responsive to Ang II,3 which suffices in tissue culture experiments not only to trigger most of the molecular features of hypertrophy but also to drive fibroblast proliferation. In clinical heart failure, this gives credence to the beneficial effects of treatments that decrease Ang II production (ACE inhibitors) or that decrease binding to its type I receptors, thereby preserving ventricular function at doses that do not lower blood pressure and consequently are thought to be mediated by blocking of local actions of this peptide.4 A second clinical setting, related but distinct, in which blockers of Ang II production or function in the heart have proven to be especially valuable is the more acute context of adverse ventricular remodeling after myocardial infarction.5 6 In the instance of Ang II, the universal caveat that a pharmacological intervention might actually work through unanticipated mechanisms has given rise to perennial controversy, because ACE inhibitors, apart from their nominal role, also impair the degradation of bradykinin.4
Given the foreseeable, recurrent, and vexing limitations of reliance on drug studies …