title: 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.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Shuxia
authors.initials: S
authors.lastname: Jiang
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Xie
authors.forename: Ang
authors.initials: A
authors.lastname: Guo
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D051244:Caveolin 3 / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D051244:Caveolin 3; D008565:Membrane Proteins; D011412:Propanolamines; C412507:junctophilin; D000077261:Carvedilol; D008790:Metoprolol