PROTEIN-KINASE-C ACTIVATION IN THE HEART - EFFECTS ON CALCIUM AND CONTRACTILE PROTEINS

Background. Cardiac contractile function is dependent on the energetic state of the heart, intracellular calcium levels, and the interaction of the contractile proteins with both adenosine triphosphate and calc ium. Protein kinase C (PKC) is a ubiquitous intracellular mediator tha t has been found in the heart and has been shown to phosphorylate prot eins that regulate calcium homeostasis (calcium channels) and the cont ractile proteins themselves (troponin I and troponin T). Methods. To d etermine the role of PKC activation on cardiac contractile function, d irect activation of PKC was achieved by the infusion of phorbol 12-myr istate 13-acetate, an activating phorbol ester. The effects of PKC act ivation were evaluated in Langendorff-perfused rabbit hearts. Contract ile function, high-energy phosphate content (phosphorous-31 nuclear ma gnetic resonance spectroscopy), oxygen consumption, and intracellular calcium levels (calcium fluorescent dye Rhod-2) were determined. Resul ts. Activation of PKC in the heart by phorbol 12-myristate 13-acetate resulted in a significant decrease in both systolic and diastolic func tion while oxygen consumption and adenosine triphosphate production re mained unchanged. Both baseline and peak intracellular calcium levels decreased, which may contribute to the impaired systolic function. Con clusions. Activation of PKC in the heart leads to significant loss of contractile function without affecting energetics. The effect is most likely due to alteration in cytosolic calcium regulation and altered c ontractile sensitivity to calcium.