| First Author | Yeh CC | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 12 | Pages | e0188471 |
| PubMed ID | 29216197 | Mgi Jnum | J:254951 |
| Mgi Id | MGI:6103681 | Doi | 10.1371/journal.pone.0188471 |
| Citation | Yeh CC, et al. (2017) Shift toward greater pathologic post-myocardial infarction remodeling with loss of the adaptive hypertrophic signaling of alpha1 adrenergic receptors in mice. PLoS One 12(12):e0188471 |
| abstractText | RATIONALE: We 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. METHODS: We 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. RESULTS: Alpha1A-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. CONCLUSIONS: Alpha1A-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. |
