Selective PKC Beta Inhibition with Ruboxistaurin and Endothelial Function in Type-2 Diabetes Mellitus

被引：58

作者：

Mehta, Nehal N. ^{[1
,2
]}

Sheetz, Matthew ^{[3
]}

Price, Karen ^{[3
]}

Comiskey, Lynn ^{[1
,2
]}

Amrutia, Shirish ^{[1
,2
]}

Iqbal, Nayyar ^{[1
,2
]}

Mohler, Emile R. ^{[1
,2
]}

Reilly, Muredach P. ^{[1
,2
]}

机构：

[1] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Dept Med, Ctr Expt Therapeut, Philadelphia, PA 19104 USA

[3] Eli Lilly Res Labs, Indianapolis, IN USA

来源：

CARDIOVASCULAR DRUGS AND THERAPY | 2009年 / 23卷 / 01期

关键词：

Type; 2; diabetes; Protein kinase C beta; Endothelial function; Oxidant stress; Macro vascular disease; PROTEIN-KINASE-C; HIGH GLUCOSE; VASCULAR COMPLICATIONS; PERIPHERAL NEUROPATHY; OXIDATIVE STRESS; NAD(P)H OXIDASE; IN-VIVO; ACTIVATION; CELL; MECHANISMS;

D O I：

10.1007/s10557-008-6144-5

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts. The goal of this double-masked, placebo-controlled trial in type-2 diabetes was to assess the effect of the PKC beta-specific inhibitor, ruboxistaurin (32 mg/day for 6 weeks) on ultrasound assessed brachial artery flow mediated dilatation (FMD), a surrogate of macro vascular endothelial function, and urinary isoprostanes, indices of oxidant stress. Compared to placebo, ruboxistaurin tended to improve FMD (difference in 6-week change in FMD, mean +/- SD millimeter) at one (0.13 +/- 0.26 mm, p = 0.08) and 5 min (0.12 +/- 0.21 mm, p = 0.02) after cuff deflation, but had no effect on nitroglycerin-mediated dilatation or urinary isoprostanes. This proof of concept trial is the first to suggest that specific inhibition of PKC beta may improve macro vascular endothelial function in type-2 diabetes. Larger trials including clinical endpoints are warranted to determine the potential efficacy of PKC beta inhibition in reducing atherosclerotic cardiovascular complications in diabetes mellitus.

引用

页码：17 / 24

页数：8

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