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 calcium. Protein kinase C (PKC) is a ubiquitous intracellular mediator that has been found in the heart and has been shown to phosphorylate proteins that regulate calcium homeostasis (calcium channels) and the contractile proteins themselves (troponin I and troponin T).


METHODS
To determine the role of PKC activation on cardiac contractile function, direct activation of PKC was achieved by the infusion of phorbol 12-myristate 13-acetate, an activating phorbol ester. The effects of PKC activation were evaluated in Langendorff-perfused rabbit hearts. Contractile function, high-energy phosphate content (phosphorous-31 nuclear magnetic resonance spectroscopy), oxygen consumption, and intracellular calcium levels (calcium fluorescent dye Rhod-2) were determined.


RESULTS
Activation of PKC in the heart by phorbol 12-myristate 13-acetate resulted in a significant decrease in both systolic and diastolic function while oxygen consumption and adenosine triphosphate production remained unchanged. Both baseline and peak intracellular calcium levels decreased, which may contribute to the impaired systolic function.


CONCLUSIONS
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 contractile sensitivity to calcium.
Buenaventura
P
P
Department of Cardiac Surgery, Children's Hospital, Boston, Massachusetts 02115, USA.
Cao-Danh
H
H
Glynn
P
P
Takeuchi
K
K
Takahashi
S
S
Simplaceanu
E
E
McGowan
F X
FX
del Nido
P J
PJ
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000032:analysis*; D003285:Contractile Proteins / Q000502:physiology*; D003593:Cytoplasm / Q000737:chemistry; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry*; D010101:Oxygen Consumption; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D011817:Rabbits
D003285:Contractile Proteins; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D002118:Calcium