PT  - JOURNAL ARTICLE
AU  - O’Connell, Timothy D.
AU  - Jensen, Brian C.
AU  - Baker, Anthony J.
AU  - Simpson, Paul C.
ED  - Insel, Paul A.
TI  - Cardiac Alpha<sub>1</sub>-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance
AID  - 10.1124/pr.112.007203
DP  - 2014 Jan 01
TA  - Pharmacological Reviews
PG  - 308--333
VI  - 66
IP  - 1
4099  - http://pharmrev.aspetjournals.org/content/66/1/308.short
4100  - http://pharmrev.aspetjournals.org/content/66/1/308.full
SO  - Pharmacol Rev2014 Jan 01; 66
AB  - 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 Gαq, and signaling through Gq, 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.