Calcitriol modulation of cardiac contractile performance via protein kinase C

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 (1 alpha,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 1,25-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 1 alpha,25-dihydroxyvitamin D-3. This dose decreased peak shortening, and accelerated contraction and relaxation rates within 5 min of administration, and changes in the Ca2+ 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 Ca2+ regulatory proteins, phospholamban, and cardiac troponin I correlated with the accelerated relaxation observed in response to acute application of 1 alpha,25-dihydroxyvitamin D-3. Accelerated relaxation continued to be observed after chronic addition of 1 alpha,25-dihydroxyvitamin D-3 (e.g. 2 days), yet this sustained increase in relaxation was not associated with increased phosphorylation of phospholamban or troponin 1. These results provide evidence that 1 alpha,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 Ca2+ regulatory proteins by this kinase contributes to the enhanced relaxation observed in response to acute, but not chronic calcitriol. (c) 2006 Elsevier Inc. All rights reserved.