title: Caveolin contributes to the modulation of basal and β-adrenoceptor stimulated function of the adult rat ventricular myocyte by simvastatin: a novel pleiotropic effect.
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.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom.
authors.forename: Sara D
authors.initials: SD
authors.lastname: Pugh
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: MacDougall
authors.affiliation: Department of Pharmacology, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Shailesh R
authors.initials: SR
authors.lastname: Agarwal
authors.affiliation: Department of Pharmacology, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: Division of Cardiovascular and Diabetes Research, University of Leeds, Leeds, West Yorkshire, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Calaghan
mesh_terms: D000328:Adult; D000818:Animals; D051244:Caveolin 3 / Q000096:biosynthesis*; D002784:Cholesterol / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000008:administration & dosage*
chemical_list: D051244:Caveolin 3; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D002784:Cholesterol; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III