Inhibition of DNA methylation attenuates low-dose cadmium-induced cardiac contractile and intracellular Ca(2+) anomalies.

(1) Cadmium is a human carcinogen with unfavourable health impacts probably associated with its DNA methylation property. Recent data suggest that environmental cadmium exposure is associated with the incidence of myocardial infarction and peripheral arterial disease. Nonetheless, the effect of chronic cadmium exposure on cardiac contractile function remains unknown. (2) The present study was designed to examine the impact of low-dose cadmium exposure on cardiac contractile function and intracellular Ca2+ homeostasis. Adult male mice were exposed to cadmium for 4 weeks (20 nmol/kg, i.p. every other day for 4 weeks) with or without the DNA methylation inhibitor 5-aza-2'-deoxyctidene (5-AZA; 0.25 mg/kg, i.p., twice a week for 6 weeks, starting at the same time as cadmium administration). Cardiac contractile and intracellular Ca2+ properties were analysed, including echocardiographic left ventricular parameters, fractional shortening (FS), peak shortening (PS) amplitude, maximal velocity of shortening/relengthening (±dL/dt), time to PS (TPS), time to 90% relengthening (TR90 ), electrically stimulated increases in intracellular Ca2+ and intracellular Ca2+ decay. (3) Cadmium exposure depressed FS, PS, ±dL/dt and electrically stimulated increases in intracellular Ca2+ without affecting TPS, TR90 , intracellular Ca2+ levels or the decay rate. The effects of cadmium were significantly attenuated (PS) or blocked altogether (all other parameters) by 5-AZA. Cadmium exposure led to overt interstitial fibrosis (collagen deposition), which was mitigated by 5-AZA treatment. Western blot analysis revealed that cadmium exposure and/or 5-AZA treatment had no effect on the expression of intercellular adhesion molecule-1, tumour necrosis factor-α and cleaved caspase 3, suggesting a relatively minor role of proinflammatory cytokines and apoptosis in the cardiac responses to cadmium and 5-AZA. (4) Together, our data demonstrate, for the first time, direct cardiac depressant effects following cadmium exposure, which may be rescued by inhibition of DNA methylation.