title: Calcitriol modulation of cardiac contractile performance via protein kinase C.
abstract: Vitamin D(3) deficiency enhances cardiac contraction in experimental studies, yet paradoxically this deficiency is linked to congestive heart failure in humans. Activated vitamin D(3) (1alpha,25-dihydroxyvitamin D(3)) or calcitriol, decreases peak force and activates protein kinase C (PKC) in isolated perfused hearts. However, the direct influence of this hormone on adult cardiac myocyte contractile function is not well understood. Our aim is to investigate whether 1alpha,25-dihydroxyvitamin D(3) acutely modulates contractile function via PKC activation in adult rat cardiac myocytes. Sarcomere shortening and re-lengthening were measured in electrically stimulated myocytes isolated from adult rat hearts, and the vitamin D(3) response (10(-10) to 10(-7) M) was compared to shortening observed under basal conditions. Maximum changes in sarcomere shortening and relaxation were observed with 10(-9) M 1alpha,25-dihydroxyvitamin D(3). This dose decreased peak shortening, and accelerated contraction and relaxation rates within 5 min of administration, and changes in the Ca(2+) transient contributed to the peak shortening and relaxation effects. The PKC inhibitor, bis-indolylmaleimide (500 nM) largely blocked the acute influence of the most potent dose (10(-9) M) on contractile function. While peak shortening and shortening rate returned to baseline within 30 min, there was a sustained acceleration of relaxation that continued over 60 min. Phosphorylation of the Ca(2+) regulatory proteins, phospholamban, and cardiac troponin I correlated with the accelerated relaxation observed in response to acute application of 1alpha,25-dihydroxyvitamin D(3). Accelerated relaxation continued to be observed after chronic addition of 1alpha,25-dihydroxyvitamin D(3) (e.g. 2 days), yet this sustained increase in relaxation was not associated with increased phosphorylation of phospholamban or troponin I. These results provide evidence that 1alpha,25-dihydroxyvitamin D(3) directly modulates adult myocyte contractile function, and protein kinase C plays an important signaling role in the acute response. Phosphorylation of key Ca(2+) regulatory proteins by this kinase contributes to the enhanced relaxation observed in response to acute, but not chronic calcitriol.
authors.affiliation: Department of Surgery, Cardiac Surgery Section, Ann Arbor, MI 48109, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Green
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Robinson
authors.forename: G E
authors.initials: GE
authors.lastname: Wilson
authors.forename: Robert U
authors.initials: RU
authors.lastname: Simpson
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Westfall
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000172:deficiency / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003971:Diastole / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000150:complications / Q000201:enzymology; D006801:Humans; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D019210:Troponin I / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000150:complications / Q000201:enzymology; D000099211:Phospholamban
chemical_list: D002117:Calcitriol; D002118:Calcium; D002135:Calcium-Binding Proteins; D011493:Protein Kinase C; D019210:Troponin I; D000099211:Phospholamban