β‐Adrenergic receptor antagonists ameliorate myocyte T‐tubule remodeling following myocardial infarction

Abstract

␤-Adrenergic receptor (AR) blockers pro-vide substantial clinical benefits, including improving overall survival and left ventricular (LV) function follow-ing myocardial infarction (MI), though the mechanisms remain incompletely defined. The transverse-tubule (T-tubule) system of ventricular myocytes is an important determinant of cardiac excitation-contraction function. T-tubule remodeling occurs early during LV failure. We hypothesized that ␤-AR blockers prevent T-tubule remod-eling and thereby provide therapeutic benefits. A murine model of MI was utilized to examine the effect of ␤-AR blockers on T-tubule remodeling following LV MI. We applied the in situ imaging of T-tubule structure from Langendorff-perfused intact hearts with laser scanning confocal microscopy. We found that MI caused remark-able T-tubule remodeling near the infarction border zone and moderate LV remodeling remote from the MI. Meto-prolol and carvedilol administered 6 d after MI for 4 wk each increased the T-tubule integrity at the remote and border zones. At the molecular level, both ␤-AR blockers restored border and remote zone expression of juncto-philin-2 (JP-2), which is involved in T-tubule organization and formation of the T-tubule/sarcoplasmic reticulum junctions. In contrast, ␤-AR blockers had no significant effects on caveolin-3 expression. In summary, our data show that ␤-AR antagonists can protect against T-tubule remodeling after MI, suggesting a novel therapeutic mechanism of action for this drug class. Preservation of JP-2 expression may contribute to the beneficial effects of metoprolol and carvedilol on T-tubule remodeling.— Chen, B., Li, Y., Jiang, S., Xie, Y.-P., Guo, A., Kutschke, W., Zimmerman, K., Weiss, R. M., Miller, F. J., Anderson, M. E., Song, L.-S. ␤-Adrenergic receptor antagonists ameliorate myocyte T-tubule remodeling following myocardial infarction. FASEB J. 26, 2531–2537 (2012). www.fasebj.org