Cardiovascular complications are the most common causes of morbidity and mortality in diabetic patients. Coronary atherosclerosis is enhanced in diabetics, whereas myocardial infarction represents 20% of deaths of diabetic subjects. Furthermore, re-infarction and heart failure are more common in the diabetics. Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a later systolic one, with intracellular retention of calcium and sodium and loss of potassium. In addition, diabetes mellitus accelerates the development of left ventricular hypertrophy in hypertensive patients and increases cardiovascular mortality and morbidity. Treating the cardiovascular problems in diabetics must be undertaken with caution. Special consideration must be given with respect to the ionic and metabolic changes associated with diabetes. For example, although ACE inhibitors and calcium channel blockers are suitable agents, potassium channel openers cause myocardial preconditioning and decrease the infarct size in animal models, but they inhibit the insulin release after glucose administration in healthy subjects. Furthermore, potassium channel blockers abolish myocardial preconditioning and increase infarct size in animal models, but they protect the heart from the fatal arrhythmias induced by ischemia and reperfusion which may be important in diabetes. For example, diabetic peripheral neuropathy usually presents with silent ischemia and infarction. Mechanistically, parasympathetic cardiac nerve dysfunction, expressed as increased resting heart rate and decreased respiratory variation in heart rate, is more frequent than the sympathetic cardiac nerve dysfunction expressed as a decrease in the heart rate rise during standing.
Decrease in intracellular thiols leads to oxidative stress and thus may cause alterations in the activity of redox-sensitive enzymes required for signal transduction, Here, we report that, N-ethylmaleimide and phenylarsine oxide, which are known to oxidize free thiols as well as protein thiols, induced phosphatidyl ethanol generation in the micromolar range suggesting activation of phospholipase D in vascular smooth muscle cells. These agents also induced significant phosphatidic acid and diacylglycerol generation without causing protein kinase C activation. Phenylarsine oxide and N-ethyl maleimide induced phosphotipase D activation is protein kinase C independent as it was not inhibited by compound-3 and bisindolylmaleimide, potent protein kinase C inhibitors. Tyrosine kinase inhibitor herbimycin A by itself activated PLD, but inhibited the phospholipase D activation by phenytarsine oxide and N-ethylmaleimide. These results suggest that oxidation of the cellular thiols activates phospholipase D independent of protein kinase C.
Reactive oxygen species function as signaling molecules, and are known to be generated under both normal and pathological conditions. Using vascular smooth muscle cells, we have demonstrated an increase in mitogen activated protein kinase activity in response to oxidants. Mitogen activated protein kinase activity increased linearly with time in cells treated with pervanadate. Hydrogen peroxide also caused rapid induction of mitogen activated protein kinase. Protein kinase C down regulation partially decreased induction of mitogen activated protein kinase activity by oxidants, and the Ca2+ ionophore, ionomycin. Protein kinase C inhibitors, compound-3 and bisindolylmaleimide did not inhibit oxidant induced mitogen activated protein kinase activity, where as calphostin C activated it. The tyrosine kinase inhibitors genistein, herbimycin A and tyrphostin caused 50% inhibition of oxidant induced mitogen activated protein kinase activation. These results suggest that oxidant-induced mitogen activated protein kinase is protein kinase C independent.
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