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.