Targeting the ACE2-Ang-(1-7) pathway in cardiac fibroblasts to treat cardiac remodeling and heart failure

Abstract Fibroblasts play a pivotal role in cardiac remodeling and the development of heart failure through the deposition of extra-cellular matrix (ECM) proteins and also by affecting cardiomyocyte growth and function. The renin–angiotensin system (RAS) is a key regulator of the cardiovascular system in health and disease and many of its effects involve cardiac fibroblasts. Levels of angiotensin II (Ang II), the main effector molecule of the RAS, are elevated in the failing heart and there is a substantial body of evidence indicating that this peptide contributes to changes in cardiac structure and function which ultimately lead to progressive worsening in heart failure. A pathway involving angiotensin converting enzyme 2 (ACE2) has the capacity to break down Ang II while generating angiotensin-(1–7) (Ang-(1–7)), a heptapeptide, which in contrast to Ang II, has cardioprotective and anti-remodeling effects. Many Ang-(1–7) actions involve cardiac fibroblasts and there is information indicating that it reduces collagen production and also may protect against cardiac hypertrophy. This report describes the effects of ACE2 and Ang-(1–7) that appear to be relevant in cardiac remodeling and heart failure and explores potential therapeutic strategies designed to increase ACE2 activity and Ang-(1–7) levels to treat these conditions. This article is part of a special issue entitled ‘‘Key Signaling Molecules in Hypertrophy and Heart Failure.’’