Cardiac pressure overload hypertrophy is differentially regulated by beta-adrenergic receptor subtypes AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Zhao, M., Fajardo, G., Urashima, T., Spin, J. M., Poorfarahani, S., Rajagopalan, V., Diem Huynh, D., Connolly, A., Quertermous, T., Bernstein, D. 2011; 301 (4): H1461-H1470

Abstract

In isolated myocytes, hypertrophy induced by norepinephrine is mediated via a(1)-adrenergic receptors (ARs) and not ß-ARs. However, mice with deletions of both major cardiac a(1)-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of ß-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of ß-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of ß(1), ß(2), or both ß(1)- and ß(2)-ARs were subjected to transverse aortic constriction (TAC). After 3 wk, ß(1)(-/-) showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas ß(2)(-/-) developed exaggerated (49% increase) hypertrophy. Only when both ß-ARs were ablated (ß(1)ß(2)(-/-)) was hypertrophy totally abolished. Cardiac function was preserved in all genotypes. Several known inhibitors of cardiac hypertrophy (FK506 binding protein 5, thioredoxin interacting protein, and S100A9) were upregulated in ß(1)ß(2)(-/-) compared with the other genotypes, whereas transforming growth factor-ß(2), a positive mediator of hypertrophy was upregulated in all genotypes except the ß(1)ß(2)(-/-). In contrast to recent reports suggesting that angiogenesis plays a critical role in regulating cardiac hypertrophy-induced heart failure, we found no evidence that angiogenesis or its regulators (VEGF, Hif1a, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both ß(1)- and ß(2)-ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy.

View details for DOI 10.1152/ajpheart.00453.2010

View details for Web of Science ID 000295360100028

View details for PubMedID 21705675

View details for PubMedCentralID PMC3197363