Local inhibition of enzyme improves endothelial vasodilatory response in heart disease patients with diabetes

Image: PD

Key study points:

1. Infusion of nor-NOHA, an inhibitor of the enzyme arginase II, improved endothelium-dependent vasodilatation in patients with coronary artery disease (CAD) CAD+ type 2 diabetes (T2DM) and CAD patients.

2. The improvement was greater in patients with CAD+T2DM and was dependent on local nitric oxide bioavailability.

Primer: Coronary artery disease (CAD) is the leading cause of death in the US and is also the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Many heart risk factors, including high cholesterol and obesity, also promote the development of T2DM. Endothelial dysfunction is among the hallmarks of both diseases. Endothelial-derived nitric oxide (NO) is thought to reduce these disease processes through its vasodilatory and anti-inflammatory effects. NO’s beneficial effects depend on its relative bioavailability, which is influenced by availability of its rate-limiting precursor L-arginine and enzymatic activity of endothelial nitric oxide synthase (eNOS).

In CAD, eNOS activity is decreased despite normal or even increased enzyme levels. In animal models and patients with advanced T2DM, levels of arginase II, an enzymatic degrader of L-arginine, are markedly elevated especially in vessel walls. Giving L-arginine to CAD patients and mouse and rabbit models of atherosclerosis failed to increase vasodilatation, suggesting that the relationship of arginine-NO metabolic pathway to vascular disease is complicated. However, in a T2DM rat model, coronary blood flow was improved by giving N(ω)-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, suggesting this may be an alternative therapeutic route for improving vascular flow in diseased vessels. The current study in Circulation translates these findings to human subjects with CAD and T2DM.

Background reading:

1. Endothelial dysfunction in insulin resistance and type 2 diabetes.

2. Arginase I contributes to diminished coronary arteriolar dilation in patients with diabetes.

3. Arginase: A Critical Regulator of Nitric Oxide Synthesis and Vascular Function.

4.  Adverse Effects of Supplemental L-Arginine in Atherosclerosis. Consequences of Methylation Stress in a Complex Catabolism?

This [phase I trial] study: 3 participant groups, 1 with CAD, 1 with CAD+T2DM, and a disease-free control group were selected (16 subjects in each). When given the arginase inhibitor N-hydroxy-nor-L-arginine (nor-NOHA), CAD patients and, to a greater extent, CAD+T2DM patients showed improved serotonin-induced vasodilatory response (up to 2-fold, P<0.0001). To confirm the role of NO availability in the observed results, a subset of 5 CAD+T2DM patients were then given both nor-NOHA and L-NMMA, an inhibitor of NO synthesis. The combination of nor-NOHA and L-NMMA averted improvement in serotonin-induced vasodilatation seen with nor-NOHA alone in these patients. No such vasodilatory improvement was seen in the control group with nor-NOHA infusion. Similar results were seen but to a lesser extent with injection of the vasodilator sodium nitroprusside.

In sum: This study demonstrated in a small number of CAD+T2DM patients that arginase II inhibition through arterial infusion of nor-NOHA could improve inducible vasodilatation in an NO-dependent manner. The improved response in the CAD+T2DM group after inhibitor infusion over the CAD-only group is consistent with the notion that arginase is specifically upregulated in the vessel endothelium of patients with diabetic macrovascular disease and suggests that nor-NOHA could hold merit as a treatment for the subset of CAD patients with diabetes.

However this study has several limitations. The study was largely underpowered and only considered males, thus limiting generalizability. Also, subject grouping did not consider the duration or extent of CAD or T2DM in the selected participants. This is especially relevant given the abundant literature suggesting endothelial dysfunction develops only after severe progression of the vascular diseases considered. In addition, differences in medication usage between the groups existed, with CAD and CAD+T2DM patients on cardiovascular and anti-diabetic medications while control patients were medication-free. These medications, such as statins and ACE inhibitors, have vasodilatory effects in addition to their primary targets thus confounding interpretation of baseline endothelial vasodilatory response. Nevertheless, the study did show improved vasodilatation relative to each CAD or CAD+T2DM patient’s baseline after nor-NOHA treatment, suggesting efficacy of the treatment. Larger, controlled studies will be needed to further evaluate this inhibitor’s therapeutic potential.

Click here to read the study in Circulation

By [SK] and [MP] 

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