Abstract
The number of people taking statins is set to increase across the globe due to recent changes in prescription guidelines. For example, half the US population over 40 is now eligible for these drugs, whether they have high serum cholesterol or not. With such development in policy comes a stronger need for understanding statins’ myriad of effects. Surprisingly little is known about possible direct actions of statins on cardiac myocytes, although claims of a direct myocardial toxicity have been made. Here, we determine the impact of simvastatin administration (40 mg/kg/day) for 2 weeks in normocholesterolemic rats on cardiac myocyte contractile function and identify an underlying mechanism. Under basal conditions, statin treatment increased the time to half (t0.5) relaxation without any effect on the magnitude of shortening, or the magnitude/kinetics of the [Ca2+]i transient. Enhanced myocyte lusitropy could be explained by a corresponding increase in phosphorylation of troponin I (TnI) at Ser23,24. Statin treatment increased expression of eNOS and Ser1177 phosphorylated eNOS, decreased expression of the NOS-inhibitory proteins caveolins 1 and 3, and increased (P = 0.06) NO metabolites, consistent with enhanced NO production. It is well-established that NO stimulates protein kinase G, one of the effectors of TnI phosphorylation at Ser23,24. Trends for parallel changes in phospho-TnI, phospho-eNOS and caveolin 1 expression were seen in atrial muscle from patients taking statins. Our data are consistent with a mechanism whereby chronic statin treatment enhances TnI phosphorylation and myocyte lusitropy through increased NO bioavailability. We see no evidence of impaired function with statin treatment; the changes we document at the level of the cardiac myocyte should facilitate diastolic filling and cardiac performance.
Highlights
Statins reduce cardiovascular morbidity and mortality and are widely prescribed to those at risk of cardiovascular disease, and with established heart disease
Simvastatin treatment increases the rate of relaxation of the cardiac myocyte, consistent with a NO-dependent modulation of troponin I (TnI) phosphorylation mediated via PKG
We have previously shown that acute simvastatin treatment of cardiac myocytes in vitro has lusitropic effects, but these were
Summary
Statins reduce cardiovascular morbidity and mortality and are widely prescribed to those at risk of cardiovascular disease, and with established heart disease. Statins inhibit the enzyme HMG CoA reductase which is the rate limiting step in cholesterol synthesis. It is well-established that the impact of statins on the cardiovascular system extends far beyond lowering serum LDL cholesterol. These ‘pleiotropic’ effects can be beneficial, and include increased NO bioavailability, anti-oxidant and anti-inflammatory actions (e.g., see, Davignon, 2004). Much research in this field has focused on endothelial cells. It is essential that the full impact of statins is understood if prevention and treatment of cardiovascular disease are to be optimized
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