Abstract
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.
Highlights
The term diabetic cardiomyopathy refers to a state of cardiac dysfunction independent of associated coronary artery disease that arises within weeks of hyperglycemia (HG) leading to longer term diabetes mellitus (DM) [1]
Given the previous findings of an upregulation of MT1a in mouse hearts after STZ injection [19], we expected a similar upregulation of metal response element-binding transcription factor-1 (MTF-1) dependent genes in the hearts of our euthyroid HG rats. (We did not examine gene expression in the hypothyroid rats due to lack of tissue.) Instead we found that HG due to STZ injection led to a significant reduction in MT1a and ZnT2 expression, similar to a downregulation of MT1a in cardiac tissue of diabetic mouse embryos [49] (Table 6)
This model may prove useful in further studies of the effects of HG and DM on cardiac cellular and molecular functions
Summary
The term diabetic cardiomyopathy refers to a state of cardiac dysfunction independent of associated coronary artery disease that arises within weeks of hyperglycemia (HG) leading to longer term diabetes mellitus (DM) [1]. Diabetic cardiomyopathy in humans and animals is Cardiomyopathic effects in rodents or rabbits with HG or type 1 DM induced by treatments targeting pancreatic β-islet cells [6,7] are characterized at the cardiomyocyte level by depressed adrenergic responsiveness [8,9], prolonged action potential duration [10,11], reduced or delayed calcium influx through sarcolemmal L-type channels [10], reduced SERCA2a content and calcium reuptake rate [11,12], greater calcium ion (Ca2+) leak through the sarcoplasmic reticulum (SR) release channels called ryanodine receptors (RyR) [13,14,15], elevated cytosolic Ca2+ in diastole [15], and reduced function yet elevated content of mitochondria [16] These and other findings indicate a broad spectrum of cellular and molecular mechanisms that underlie the elevated morbidity and mortality associated with diabetic cardiomyopathy [1,2]. The balance of calcium and zinc regulation would be a logical focus of inquiry in determining the underling mechanisms responsible for the protective effects of zinc during the development of diabetic cardiomyopathy
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