title: Cardiac pressure overload hypertrophy is differentially regulated by β-adrenergic receptor subtypes.
abstract: In isolated myocytes, hypertrophy induced by norepinephrine is mediated via α(1)-adrenergic receptors (ARs) and not β-ARs. However, mice with deletions of both major cardiac α(1)-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of β-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of β-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of β(1), β(2), or both β(1)- and β(2)-ARs were subjected to transverse aortic constriction (TAC). After 3 wk, β(1)(-/-) showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas β(2)(-/-) developed exaggerated (49% increase) hypertrophy. Only when both β-ARs were ablated (β(1)β(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 β(1)β(2)(-/-) compared with the other genotypes, whereas transforming growth factor-β(2), a positive mediator of hypertrophy was upregulated in all genotypes except the β(1)β(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, Hif1α, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both β(1)- and β(2)-ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California 94304, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Takashi
authors.initials: T
authors.lastname: Urashima
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Sara
authors.initials: S
authors.lastname: Poorfarahani
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Rajagopalan
authors.forename: Diem
authors.initials: D
authors.lastname: Huynh
authors.forename: Andrew
authors.initials: A
authors.lastname: Connolly
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D003251:Constriction, Pathologic / Q000503:physiopathology; D004562:Electrocardiography; D055106:Genome-Wide Association Study; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D016612:Paraffin Embedding; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D012313:RNA