In This Issue of Diabetes

Edited by Helaine E. Resnick, PhD, MPH

Coronary Microvascular Dysfunction Linked to Endothelial Caveolae Disruption and NOS Uncoupling

Impaired myocardial perfusion is a forerunner of cardiovascular events and is therefore an appealing therapeutic target. A study in this issue of Diabetes (p. 1381) provides novel evidence that reduced flow-mediated dilation (FMD)—the degree of vasodilation in response to increasing wall shear stress—in the coronary arterioles of diabetic patients results from peroxynitrite (ONOO-) targeting of endothelial caveolae, a type of lipid raft whose primary functional protein is caveolin. Nitric oxide (NO), a critical regulator of vasodilation, is produced by nitric oxide synthase (NOS). When NO synthesis is derailed by ONOO-, a process called NOS uncoupling, the result is impeded resistance arterial flow. To better characterize the mechanism of endothelial NOS uncoupling in diabetes, Cassuto et al. examined FMD in coronary arterioles of 41 diabetic and 37 nondiabetic patients at the time of heart surgery. Their results show that coronary arteries of diabetic patients exhibited reduced FMD and enhanced ONOO- levels. Further, the investigators demonstrated that the location of ONOO- production in the diabetic endothelium overlapped with membrane regions that contained caveolin-1, an observation suggesting that ONOO- targets the caveolae. In a series of intriguing experiments, the investigators varied levels of ONOO- and BH4 (tetrahydrobiopterin, an NOS cofactor) and assessed coronary FMD in response to these changes. Exogenous ONOO- significantly reduced the number of endothelial caveolae in diabetic patients in a dose-dependent manner and also decreased FMD in nondiabetic patients. To solidify their findings, the investigators showed that sequestering excess ONOO- in diabetic patients restored FMD. In diabetic arteries, incubation with sepiapterin, a BH4 precursor, improved FMD, whereas no effect was observed in the nondiabetic patients. Notably, FMD loss following administration of methyl-β-cyclodextrin (mβCD)—which is known to disrupt caveolae—was reversed and FMD was …

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This Article

  1. doi: 10.2337/db14-ti04 Diabetes vol. 63 no. 4 1167-1168
  1. Free via Open Access: OA