Arsenic is a common contaminant in drinking water throughout the world, and recent studies support a link between inorganic arsenic (iAS) exposure and ischemic heart disease in men and women. Female hearts exhibit an estrogen-dependent reduction in susceptibility to myocardial ischemic injury compared with males, and as such, female hearts may be more susceptible to the endocrine-disrupting effects of iAS exposure. However, iAS exposure and susceptibility to ischemic heart injury have not been examined in mechanistic studies. Male and female mice (8 wk) were exposed to environmentally relevant concentrations of sodium arsenite (0, 10, 100, and 1,000 parts/billion) via drinking water for 4 wk. Pre- and postexposure echocardiography was performed, and postexposure plasma was collected for 17β-estradiol measurement. Hearts were excised and subjected to ischemia-reperfusion (I/R) injury via Langendorff perfusion. Exposure to 1,000 parts/billion iAS led to sex-disparate effects, such that I/R injury was exacerbated in female hearts but unexpectedly attenuated in males. Assessment of echocardiographic parameters revealed statistically significant structural remodeling in iAS-treated female hearts with no change in function; males showed no change. Plasma 17β-estradiol levels were not significantly altered by iAS in male or female mice versus nontreated controls. Although total eNOS protein levels did not change in whole heart homogenates from iAS-treated male or female mice, eNOS phosphorylation (Ser1177) was significantly elevated in iAS-treated male hearts. These results suggest that iAS exposure can induce sex-disparate effects and modulate susceptibility to ischemic heart injury by targeting distinct sex-dependent pathways. NEW & NOTEWORTHY This is the first mechanistic study examining iAS exposure on myocardial ischemia-reperfusion injury in male and female mice. Following iAS exposure, ischemia-reperfusion injury was exacerbated in female hearts but attenuated in males. iAS treatment induced statistically significant cardiac remodeling in females, with no change in males. iAS treatment also enhanced phosphorylated eNOS levels at Ser1177, but only in male hearts. These results suggest that iAS alters susceptibility to myocardial I/R injury through distinct sex-dependent pathways.

Arsenic exposure through drinking water is widespread and well-associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which inorganic arsenic (iAS) induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independent of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Adult male and female C56BL/6J mice were exposed to 615 μg/L iAS for eight weeks. Males exhibited increased systolic blood pressure via tail cuff photoplethysmography, left ventricular wall thickening via transthoracic echocardiography, and increased plasma atrial natriuretic peptide via enzyme immunoassay. RT-qPCR revealed increased myocardial RNA transcripts of Acta1, Myh7, and Nppa, and decreased Myh6, providing evidence of pathological hypertrophy in the male heart. Similar changes were not detected in females, and nitric oxide dependent mechanisms of cardioprotection in the heart appeared to remain intact. Further investigation found that Rcan1 was upregulated in male hearts and that iAS activated NFAT in HEK293 cells via luciferase assay. Interestingly, iAS induced similar hypertrophic gene expression changes in neonatal rat ventricular myocytes, which were blocked by calcineurin inhibition, suggesting that iAS may induce pathological cardiac hypertrophy in part by targeting the calcineurin-NFAT pathway. As such, these results highlight iAS exposure as an independent cardiovascular risk factor and provide biological impetus for its removal from human consumption.

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