Exposure to inorganic arsenic (iAS) through drinking water is well-associated with adverse cardiovascular outcomes, yet the mechanisms through which it induces these effects are not fully understood. Recent epidemiological findings highlight an association between iAS exposure and altered left ventricular geometry in both the presence and absence of hypertension. We therefore tested the hypothesis that iAS exposure has a bimodal impact on cardiac-intrinsic and hemodynamic mechanisms that together induce pathological remodeling of the myocardium. Adult male and female mice were exposed to an environmentally relevant dose of 615 μg/L NaAsO
2
for eight weeks. Males (n=9-10 mice/group) exhibited increased systolic blood pressure (115.1±3.0 vs. 106.0±2.3 mmHg, p=0.0350) via tail cuff photoplethysmography, left ventricular wall thickening (0.98±0.01 vs. 0.88±0.01 mm, p<0.0001) via transthoracic echocardiography, increased heart weight to tibia length (8.56±0.21 vs. 7.15±0.24 mg/mm; n=24 mice/group), and increased plasma atrial natriuretic peptide (47.85±12.0 vs. 15.14±3.73 pg/mL, p=0.0379) via enzyme immunoassay. Myocardial mRNA transcript levels (n=10 hearts/group) of
Acta1
(1.36±0.18 vs. 0.73±0.11, p=0.0037),
Myh7
(1.53±0.15 vs. 1.04±0.10, p=0.0138), and
Nppa
(2.40±0.29 vs. 1.02±0.07, p=0.0001) were increased, and
Myh6
(0.92±0.17 vs. 1.14±0.23, p=0.0001) was decreased, evidencing pathological hypertrophy in the male heart. Female hearts, however, were largely protected at this eight-week timepoint as similar changes were not detected. Further investigation found that
Rcan1
was upregulated (1.47±0.19 vs. 0.97±0.04, p=0.0161; n=10 hearts/group) in male hearts, suggesting that calcineurin-NFAT was activated. Interestingly, iAS was sufficient to activate NFAT (0.82±0.11 vs. 0.46±0.05, p=0.0214; n=8 wells/group) independent of blood pressure via luciferase assay. In conclusion, these results demonstrate for the first time that iAS may cause pathological cardiac hypertrophy not only by increasing hemodynamic load, but also by activating calcineurin-NFAT and inducing fetal gene expression in the male heart, thus providing novel mechanistic insight into the threat of iAS exposure to the cardiovascular system.
DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress
