RESUMEN
Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1 MyHC6 ). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism both in vivo and in vitro . In vitro , treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1 MyHC6 mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1 MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45 + ), particularly neutrophils (CD11b + , Ly6g + ), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.
RESUMEN
A primary cause of bioprosthetic heart valve failure is premature degeneration of the pericardial leaflets, owing specifically to mechanical fatigue. There remains a paucity of experimental data and understanding of the fatigue-damage behaviour of this collagenous tissue under complex loading regimes. To meet this knowledge gap, a novel pressure inflation system was designed and built, to cyclically load circular samples of glutaraldehyde fixed bovine pericardium, under equibiaxial bulge conditions. A study up to 60 million cycles revealed new insights into the fatigue behaviour of pericardial tissue, where a statistically significantly higher level of permanent set was found in samples with high collagen fibre dispersion, in comparison to those with highly aligned fibres. Whilst permanent set is known to occur in the non-collagenous matrix of pericardium, this study demonstrates that at physiological loads, which elicit a matrix dominant mechanical response, permanent set and thus tissue-level damage, is still mediated by the underlying collagen fibres.
