Introduction:
Coronary microvascular dysfunction is prevalent among diabetics and intersects with deficits in endothelial-dependent vasodilation. These deficits occur early in the progression of the disease, but the mechanisms remain incompletely understood. Nitric oxide (NO) is the major endothelial-dependent mediator of vasodilation in the healthy coronary circulation, but the mediator switches to hydrogen peroxide (H
2
O
2
) in coronary artery disease (CAD) patients.
Diabetes is a risk factor for CAD, so we hypothesized that a similar switch would occur.
Methods:
Coronary arteries were isolated and endothelial-dependent vasodilation was assessed using myography. Quantitative polymerase chain reaction (qPCR) was performed for gene expression analysis and myocardial blood flow (MBF) was measured by contrast echocardiography.
Results:
Nitric oxide synthase inhibitor (L-NAME) inhibited vasodilation in wild type (WT) mice, but the H
2
O
2
scavenger (PEG-catalase) had no effect. In contrast, vasodilation in diabetic mice was blunted by PEG-catalase, but not L-NAME. This suggests that the mediator of coronary vasodilation switched from NO to H
2
O
2
in diabetes. Importantly, we found that microRNA-21 (miR-21) is upregulated in diabetes and the deficiency modulates the mediator switch from NO to H
2
O
2
in diabetic mice.
Conclusions:
The switch in the mediator of coronary vasodilation from NO to H2O2 contributes to microvascular dysfunction in diabetes and miR-21 regulates this switch. Further genetic profiling will elucidate the pathways and mechanisms converging with miR-21 to regulate microvascular function in diabetes. This is the first mouse model that recapitulates the switch in mediator of coronary vasodilation from NO to H
2
O
2
seen in CAD patients.
Chloroquine differentially modulates coronary vasodilation in control and diabetic mice
