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.

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

“…We were surprised by how dramatically elongated 3-to 5-week-old Tg8a and Tg8b cardiomyocytes were, with less abundant, disarrayed transverse tubules (T-tubules) compared with those of WT hearts ( Figure 4, A-E). Tg8a cardiomyocytes were 42% longer and 27% thinner than WT littermates and contained 68% less organized T-tubules, as determined through T-tubular power spectrum analysis (33). The decrease in T-tubule organization is sufficient to explain the Ca 2+ handling defects, as T-tubules are critical for efficient Ca 2+ -induced Ca 2+ release and excitation-contraction coupling.…”

Selective Modulation of Coupled Ryanodine Receptors During Microdomain Activation of Calcium/Calmodulin-Dependent Kinase II in the Dyadic Cleft

“…[4][5][6] Recent studies have started to document the timeline of such changes during the transition from hypertrophy to heart failure 7 and the potential for reversal. 8,9 We have recently started to investigate whether the intrinsic properties of RyR subpopulations that are coupled or at a distance of TT are different, by studying spontaneous RyR opening events at rest in release sites that were close to TT or at a distance. 10 Ca 2+ sparks were more frequent in sites close to TT, and this was not dependent on activity of LTCC, but a clear mechanism could not be identified.…”

Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes

“…Moreover, mutations in the JP2 coding region have been discovered in patients with hypertrophic cardiomyopathy (13,14). The pathological relevance of JP2 has been revealed by observations that dysregulation of JP2 protein is associated with pathological progression in multiple models of heart failure, including pressure overload-induced hypertrophy/heart failure and myocardial infarction (15)(16)(17)(18)(19)(20)(21). Toward understanding the mechanism of JP2 down-regulation, a recent report has demonstrated that JP2 is targeted by the microRNA miR-24, which may be responsible for the down-regulation of JP2 during long-term pressure overload-induced hypertrophy and heart failure (19,22).…”