Investigation of the pathophysiological significance of big mitogen-activated protein kinase 1 in diabetic microangiopathy for the development of molecular-targeted drugs

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In the current research project, we investigated the pathophysiological significance of big mitogen-activated protein kinase 1 in diabetic microangiopathy for the development of molecular-targeted drugs.1)In the type 2 diabetic rat model OLETF, BMK1 was activated in the small artery at 30 weeks of age without apparent complications with diabetes mellitus. From these findings, it was suggested that BMK1 activation is involved in the pathogenesis of diabetic microangiopathy.2)In the mouse model of inflammatory vascular disease, big mitogen-activated protein kinase 1 (BMK1) was activated at the site of adventitia of cuff-injured femoral artery. At the site of cuff-injured artery, neointimal formation and infiltration of mononuclear cells were observed. These findings suggest that BMK1 is involved in the pathogenesis of inflammatory vascular remodeling.3)In experiments using cultured rat aortic smooth muscle cells (RASMC), aldosterone stimulated BMK1 activation. BMK1 activation by aldosterone was inhibited by treatment with eplerenone, a mineralocorticoid receptor blocker. Aldosterone-induced RASMC proliferation was inhibited by genetic BMK1 inhibition.4)In RASMC PDGF stimulated BMK1 activation in a time and concentration-dependent manner. PDGF also stimulated RASMC migration, which was inhibited by a transfection with dominant-negative MEK5.From these in vivo and in vitro findings, BMK1 is suggested to be involved in diabetic microangiopathy and BMK1 may be one of the drug targets for treatment of complications with diabetes mellitus.