Abstract

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha₁-ARs signal through Gα_q, and signaling through G_q, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha₁-ARs mediate important protective and adaptive functions in the heart, although alpha₁-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha₁-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha₁-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha₁-AR expression is similar to that in the mouse, where alpha₁-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha₁-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha₁-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha₁-AR function and suggest that activation of cardiac alpha₁-AR might be a viable therapeutic strategy in heart failure.