Abstract
The number of people taking statins is increasing across the globe, highlighting the importance of fully understanding statins' effects on the cardiovascular system. The beneficial impact of statins extends well beyond regression of atherosclerosis to include direct effects on tissues of the cardiovascular system (‘pleiotropic effects’). Pleiotropic effects on the cardiac myocyte are often overlooked. Here we consider the contribution of the caveolin protein, whose expression and cellular distribution is dependent on cholesterol, to statin effects on the cardiac myocyte. Caveolin is a structural and regulatory component of caveolae, and is a key regulator of cardiac contractile function and adrenergic responsiveness. We employed an experimental model in which inhibition of myocyte HMG CoA reductase could be studied in the absence of paracrine influences from non-myocyte cells. Adult rat ventricular myocytes were treated with 10 µM simvastatin for 2 days. Simvastatin treatment reduced myocyte cholesterol, caveolin 3 and caveolar density. Negative inotropic and positive lusitropic effects (with corresponding changes in [Ca2+]i) were seen in statin-treated cells. Simvastatin significantly potentiated the inotropic response to β2-, but not β1-, adrenoceptor stimulation. Under conditions of β2-adrenoceptor stimulation, phosphorylation of phospholamban at Ser16 and troponin I at Ser23/24 was enhanced with statin treatment. Simvastatin increased NO production without significant effects on eNOS expression or phosphorylation (Ser1177), consistent with the reduced expression of caveolin 3, its constitutive inhibitor. In conclusion, statin treatment can reduce caveolin 3 expression, with functional consequences consistent with the known role of caveolae in the cardiac cell. These data are likely to be of significance, particularly during the early phases of statin treatment, and in patients with heart failure who have altered β-adrenoceptor signalling. In addition, as caveolin is ubiquitously expressed and has myriad tissue-specific functions, the impact of statin-dependent changes in caveolin is likely to have many other functional sequelae.
Highlights
The number of people taking statins will increase as the threshold for statin prescription in cardiovascular disease prevention continues to decrease across the globe
Our first question was whether culturing myocytes in the presence of simvastatin reduces cellular cholesterol i.e. does simvastatin reduce de novo myocyte cholesterol synthesis? In order to select a concentration of simvastatin which is of clinical relevance, we considered serum levels of drug, tissue accumulation and IC50
In preliminary studies we compared the effect of 1 mM and 10 mM simvastatin treatment on myocyte free cholesterol indexed using the fluorescent antibiotic filipin
Summary
The number of people taking statins will increase as the threshold for statin prescription in cardiovascular disease prevention continues to decrease across the globe. Recent amendments to ACC/AHA guidelines for statin prescription [1] mean that 13 million more individuals, and a total of 49% of adults between 40 and 75, are eligible for statin therapy in the US [2]. [3]), highlights the importance of fully understanding statins’ effects on the cardiovascular system. Clinical and experimental data support the view that the impact of statins on the cardiovascular system extends well beyond lowering serum LDL cholesterol; many of their beneficial effects can be ascribed to direct actions on tissues of the cardiovascular system (‘pleiotropic’ effects). Little work has focused on direct effects of statins on the cardiac myocyte
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