Abstract
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, P<0.05) but decreased phospho-ERK1/2 post-MI (0.49 ± 0.35 arbitrary units vs. 1.55 ± 0.43 in WT, P<0.05). Furthermore, expression of pro-apoptotic factor Bax was increased (1.19 ± 0.15 vs. 0.78 ± 0.08, P<0.05) and expression of anti-apoptotic factors Bcl2 was decreased (0.26 ± 0.01 vs. 0.55 ± 0.06, P<0.01) compared to WT.ConclusionsAlpha1A-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.
Highlights
Alpha1A-adrenergic receptors (ARs) knockout paradoxically increased post-myocardial infarction (MI) hypertrophy compared to wild type controls (WT), and increased ventricular dilatation, fibrosis, apoptosis, and 4-week postMI 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, P
We have hypothesized that a dynamic balance exists between signaling pathways during the heart’s response to various stresses, with pro-adaptive pathways dominating in the context of physiologic hypertrophy, and greater mal-adaptive signaling resulting in eventual decompensatory changes [1,2]
Pro-survival and pro-adaptive MEK1/2-ERK1/2 mitogen activated protein (MAP) kinase signaling has been associated with alpha1A-AR in the myocardium, and the impact of deletion of this receptor on mitogen activated protein kinase (MAPK) signaling was investigated
Summary
We have hypothesized that a dynamic balance exists between signaling pathways during the heart’s response to various stresses, with pro-adaptive pathways dominating in the context of physiologic hypertrophy (e.g. in response to exercise or pregnancy), and greater mal-adaptive signaling resulting in eventual decompensatory changes (e.g. in pressure overload or postinfarction cardiomyopathy) [1,2] Such a dynamic balance creates an opportunity for more precise design of molecular interventions for progressive, often intractable heart failure, one of the largest single sources of morbidity and mortality in the United States. Studies using the alpha1A knockout mouse model showed that these specific receptors are required for physiological cardiac hypertrophy [10] The deletion of both alpha1A and alpha1B receptors resulted in an exacerbation of the maladaptive response to pressure overload, with increases in apoptosis, dilated cardiomyopathy, and death, suggesting that they might play an ameliorative role counterbalancing other pathologic stimulation. Gain-of-function studies have documented that enhanced inotropy from transgenic alpha1A-AR overexpression prevents remodeling of the left ventricle (LV), preserves function, and reduces acute heart failure death after MI or induction of pressure overload [14,15]
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