Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform

Cardiovascular Diabetology

Original Investigation

Sarah M Tremble¹  Yaser Cheema¹  Stephen P Bell¹  Zengyi Chen¹  Meenakumari Subramanian²  Ting Yi²  Bradley M Palmer²  Peter VanBuren³  Martin M LeWinter³ 

[1] Department of Medicine, University of Vermont, 05405, Burlington, VT, USA;Department of Molecular Physiology and Biophysics, University of Vermont, 122 HSRF Beaumont Ave, 05405, Burlington, VT, USA;Department of Molecular Physiology and Biophysics, University of Vermont, 122 HSRF Beaumont Ave, 05405, Burlington, VT, USA;Department of Medicine, University of Vermont, 05405, Burlington, VT, USA;

关键词: Streptozotocin;    PTU;    Type 1 diabetes;    Cardiac;    Iron;    Sulfur;   

DOI  :  10.1186/1475-2840-11-135

 received in 2012-08-28, accepted in 2012-10-20,  发布年份 2012

来源: Springer

【 摘 要 】

It has been reported previously that diabetic cardiomyopathy can be inhibited or reverted with chronic zinc supplementation. In the current study, we hypothesized that total cardiac calcium and zinc content is altered in early onset diabetes mellitus characterized in part as hyperglycemia (HG) and that exposure of zinc ion (Zn2+) to isolated cardiomyocytes would enhance contraction-relaxation function in HG more so than in nonHG controls. To better control for differential cardiac myosin isoform expression as occurs in rodents after β-islet cell necrosis, hypothyroidism was induced in 16 rats resulting in 100% β-myosin heavy chain expression in the heart. β-Islet cell necrosis was induced in half of the rats by streptozocin administration. After 6 wks of HG, both HG and nonHG controls rats demonstrated similar myofilament performance measured as thin filament calcium sensitivity, native thin filament velocity in the myosin motility assay and contractile velocity and power. Extracellular Zn2+ reduced cardiomyocyte contractile function in both groups, but enhanced relaxation function significantly in the HG group compared to controls. Most notably, a reduction in diastolic sarcomere length with increasing pacing frequencies, i.e., incomplete relaxation, was more pronounced in the HG compared to controls, but was normalized with extracellular Zn2+ application. This is a novel finding implicating that the detrimental effect of HG on cardiomyocyte Ca2+ regulation can be amelioration by Zn2+. Among the many post-translational modifications examined, only phosphorylation of ryanodine receptor (RyR) at S-2808 was significantly higher in HG compared to nonHG. We did not find in our hypothyroid rats any differentiating effects of HG on myofibrillar protein phosphorylation, lysine acetylation, O-linked N-acetylglucosamine and advanced glycated end-products, which are often implicated as complicating factors in cardiac performance due to HG. Our results suggest that the relaxing effects of Zn2+ on cardiomyocyte function are more pronounced in the HG state due an insulin-dependent effect of enhancing removal of cytosolic Ca2+ via SERCA2a or NCX or by reducing Ca2+ influx via L-type channel or Ca2+ leak through the RyR. Investigations into the effects of Zn2+ on these mechanisms are now underway.

【 授权许可】

Unknown   
© Yi et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.