Shift toward greater pathologic post-myocardial infarction remodeling with loss of the adaptive hypertrophic signaling of alpha1 adrenergic receptors in mice

RationaleWe have hypothesized that post-infarction cardiac remodeling can be influenced by shifts in the balance between intracellular mediators of “pathologic” and “physiologic” hypertrophy. Although alpha1 adrenergic receptors (alpha1-ARs) mediate pro-adaptive hypertrophy during pressure overload, little is known about their role or downstream mediators after myocardial infarction.MethodsWe performed loss-of-function experiments via coronary ligation in alpha1A-AR knockout (AKO) mice. Post-myocardial infarction (MI) remodeling was evaluated via echocardiography, quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of cardiac fetal gene expression, histologic analysis of myocyte size, post-MI fibrosis and apoptosis, and Western blot analysis of apoptotic regulators.ResultsAlpha1A-AR knockout paradoxically increased post-MI hypertrophy compared to wild type controls (WT), but also increased ventricular dilatation, fibrosis, apoptosis, and 4-week post-MI mortality (64% in AKO vs. 25% in WT, P = 0.02), suggesting a shift toward greater pathologic hypertrophy in the absence of pro-adaptive alpha1A effects. alpha1A-AR knockout increased phospho-p38 levels in the pre-MI myocardium compared to WT (0.55 ± 0.16 vs. 0.03 ± 0.01, PConclusionsAlpha1A-AR provides an important counterbalance to pathologic pathways during post-MI remodeling that may be mediated through ERK1/2 signaling; these observations provide support for further development of an alpha1A-AR/ERK-based molecular intervention for this chronic, often fatal disease.