Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity

Abstract

Caveolae and associated cavin and caveolins may govern myocardial function, together with responses to mechanical and ischaemic stresses. Abnormalities in these proteins are also implicated in different cardiovascular disorders. However, specific roles of the cavin-1 protein in cardiac and coronary responses to mechanical/metabolic perturbation remain unclear. We characterised cardiovascular impacts of cavin-1 deficiency, comparing myocardial and coronary phenotypes and responses to stretch and ischaemia–reperfusion in hearts from cavin-1+/+ and cavin-1−/− mice. Caveolae and caveolins 1 and 3 were depleted in cavin-1−/− hearts. Cardiac ejection properties in situ were modestly reduced in cavin-1−/− mice. While peak contractile performance in ex vivo myocardium from cavin-1−/− and cavin-1+/+ mice was comparable, intrinsic beating rate, diastolic stiffness and Frank–Starling behaviour (stretch-dependent diastolic and systolic forces) were exaggerated in cavin-1−/− hearts. Increases in stretch-dependent forces were countered by NOS inhibition (100 µM L-NAME), which exposed negative inotropy in cavin-1−/− hearts, and were mimicked by 100 µM nitroprusside. In contrast, chronotropic differences appeared largely NOS-independent. Cavin-1 deletion also induced NOS-dependent coronary dilatation, ≥3-fold prolongation of reactive hyperaemic responses, and exaggerated pressure-dependence of coronary flow. Stretch-dependent efflux of lactate dehydrogenase and cardiac troponin I was increased and induction of brain natriuretic peptide and c-Fos inhibited in cavin-1−/− hearts, while ERK1/2 phospho-activation was preserved. Post-ischaemic dysfunction and damage was also exaggerated in cavin-1−/− hearts. Diverse effects of cavin-1 deletion reveal important roles in both NOS-dependent and -independent control of cardiac and coronary functions, together with governing sarcolemmal fragility and myocardial responses to stretch and ischaemia.