Targeting metabolic pathways as an effective strategy to improve vascular and muscular fitness in diabetic peripheral ischaemia

We propose to test the novel hypothesis that restoring metabolic flexibility of angio-myogenic cells through modulation of PKCβ and/or PPARβ/δ activity will greatly improve the outcome of diabetic vascular disease. In preliminary studies, we have found that diabetes impinges upon key biological functions of human muscular pericytes (MPs), a principal angio-myogenic cell population. We discovered that hyperglycaemia-associated oxidative stress induces PKCβ activity in diabetic MPs leading to phosphorylation of mitochondrial adaptor protein Shc1, isoform p66 (p66Shc), a major regulator of redox homeostasis. Inhibition of PKCβ restores MP proliferation and myogenic differentiation and abrogates diabetic MPs anti-angiogenic activity. These data prompt us to test the therapeutic activity of PKCβ inhibitors in a diabetic animal model of peripheral ischaemia. PKCβ inhibitors will be tested alone or in association with a PPARβ/δ agonist to achieve a global metabolic control. We expect that this combinatory approach will benefit regenerative processes at vascular and muscular level.

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