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

Abstract

β-Adrenergic receptor (AR) blockers provide substantial clinical benefits, including improving overall survival and left ventricular (LV) function following 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 β-AR blockers prevent T-tubule remodeling and thereby provide therapeutic benefits. A murine model of MI was utilized to examine the effect of β-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 remarkable T-tubule remodeling near the infarction border zone and moderate LV remodeling remote from the MI. Metoprolol 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 β-AR blockers restored border and remote zone expression of junctophilin-2 (JP-2), which is involved in T-tubule organization and formation of the T-tubule/sarcoplasmic reticulum junctions. In contrast, β-AR blockers had no significant effects on caveolin-3 expression. In summary, our data show that β-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.

• Authors: Biyi Chen, Yue Li, Shuxia Jiang, Yu-Ping Xie, Ang Guo, William Kutschke, Kathy Zimmerman, Robert M Weiss, Francis J Miller, Mark E Anderson, Long-Sheng Song
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 26 Issue 6 Pg. 2531-7 (Jun 2012) ISSN: 1530-6860 [Electronic] United States
• PMID: 22375019 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Carbazoles
• Caveolin 3
• Membrane Proteins
• Propanolamines
• junctophilin
• Carvedilol
• Metoprolol

Topics

• Adrenergic beta-Antagonists (pharmacology, therapeutic use)
• Animals
• Carbazoles (pharmacology)
• Carvedilol
• Caveolin 3 (biosynthesis)
• Male
• Membrane Proteins (biosynthesis)
• Metoprolol (pharmacology)
• Mice
• Myocardial Infarction (drug therapy, physiopathology)
• Myocytes, Cardiac (drug effects, physiology)
• Propanolamines (pharmacology)
• Ventricular Remodeling (drug effects, physiology)