Requisite roles of LOX-1, JNK, and arginase in diabetes-induced endothelial vasodilator dysfunction of porcine coronary arterioles
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Diabetes is associated with cardiac inflammation and impaired endothelium-dependent coronary vasodilation, but molecular mechanisms involved in this dysfunction remain unclear. We examined contributions of inflammatory molecules lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), stress-activated kinases (c-Jun N-terminal kinase [JNK] and p38), arginase, and reactive oxygen species to coronary arteriolar dysfunction in a porcine model of type 1 diabetes. Coronary arterioles were isolated from streptozocin-induced diabetic pigs and control pigs for vasoreactivity and molecular/biochemical studies. Endothelium-dependent nitric oxide (NO)-mediated vasodilation to serotonin was diminished after 2 weeks of diabetes, without altering endothelium-independent vasodilation to sodium nitroprusside. Superoxide scavenger TEMPOL, NO precursor L-arginine, arginase inhibitor nor-NOHA, anti-LOX-1 antibody or JNK inhibitors SP600125 and BI-78D3 improved dilation of diabetic vessels to serotonin. However, hydrogen peroxide scavenger catalase, anti-IgG antibody or p38 kinase inhibitor SB203580 had no effect. Combined inhibition of arginase and superoxide levels did not further improve vasodilation. Arginase-I mRNA expression, LOX-1 and JNK protein expression, and superoxide levels were elevated in diabetic arterioles. In conclusion, sequential activation of LOX-1, JNK, and L-arginine consuming enzyme arginase-I in diabetes elicits superoxide-dependent oxidative stress and impairs endothelial NO-mediated dilation in coronary arterioles. Therapeutic targeting of these adverse vascular molecules may improve coronary arteriolar function during diabetes.
author list (cited authors)
Hein, T. W., Xu, X., Ren, Y. i., Xu, W., Tsai, S., Thengchaisri, N., & Kuo, L.