Inhibition of PKC beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy

Kevin Connelly, D Kelly, Ying Zhang, David L Prior, Henry Krum, Richard E Gilbert

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Abstract

Background: Diabetic cardiomyopathy (DCM) is increasingly recognized as contributing to the morbidity and mortality of diabetic patients. We have recently demonstrated that the (mRen-2)27 transgenic rat (Ren-2) develops the haemodynamic and structural changes of DCM when diabetes is induced with streptozotocin (STZ). While multifactorial in its pathogenesis, the β isoform of protein kinase C (PKC) has been recently implicated as a central mediator in the development of diabetic complications. Accordingly, we hypothesized that its inhibition with the orally active, selective inhibitor of PKC-beta, ruboxistaurin (RBX) would preserve cardiac function and reduce collagenous matrix deposition. Methods: Six week-old homozygous Ren-2 (n=34) rats were randomized to receive STZ (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Two days post STZ injection, when diabetes was confirmed, rats were further randomized to vehicle or RBX at 20mg/kg daily. Insulin (2–4 units x3 per week) was used to promote weight gain and reduce mortality. Prior to tissue collection, animals underwent in-vivo cardiac catheterization with pressure-volume loop acquisition. Results: Blood glucose was elevated in the diabetic group (p<0.01), as were levels of the PKC βisoform. Compared with untreated diabetic rats, RBX-treated Ren-2 diabetic animals demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work (PRSW) relationship (p<0.05), and the slope of the end-diastolic pressure volume relationship (p<0.01). Collagen I and III levels were also reduced in RBX treated Ren-2 diabetic animals (p<0.01). Cardiomyocyte hypertrophy and high levels of transforming growth factor-beta (TGF beta) along with phospho-Smad2 (a marker of TGF beta activity), were similarly reduced in RBX-treated animals (p<0.01). In contrast, no changes were seen in non-diabetic animals. Conclusions: Inhibition of PKC beta isoform with RBX in the diabetic Ren-2 rat preserves systolic and diastolic function and attenuates extracellular matrix accumulation, along with a reduction in the prosclerotic cytokine TGF beta. PKC-beta inhibition may present a novel therapeutic strategy for the treatment and/or prevention of DCM.
Original languageEnglish
Article numberAbstract 3922
Pages (from-to)843-843
Number of pages1
JournalCirculation
Volume114
Issue numbersuppl 18
Publication statusPublished - 31 Oct 2006

Cite this

Connelly, K., Kelly, D., Zhang, Y., Prior, D. L., Krum, H., & Gilbert, R. E. (2006). Inhibition of PKC beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circulation, 114(suppl 18), 843-843. [Abstract 3922].