Title: Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart.

Authors: Kabir, Raihan; Sinha, Prithvi; Mishra, Sumita; Ebenebe, Obialunanma V; Taube, Nicole; Oeing, Chistian U; Keceli, Gizem; Chen, Rui; Paolocci, Nazareno; Rule, Ana; Kohr, Mark J

Published In Am J Physiol Heart Circ Physiol, (2021 04 01)

Abstract: Arsenic exposure though drinking water is widespread and well associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which 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 independently 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 8 wk. 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 HEK-293 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.NEW & NOTEWORTHY This investigation provides the first mechanistic link between an environmentally relevant dose of inorganic arsenic (iAS) and pathological hypertrophy in the heart. By demonstrating that iAS exposure may cause pathological cardiac hypertrophy not only by increasing systolic blood pressure but also by potentially activating calcineurin-nuclear factor of activated T cells and inducing fetal gene expression, these results provide novel mechanistic insight into the theat of iAS exposure to the heart, which is necessary to identify targets for medical and public health intervention.

PubMed ID: 33481702

MeSH Terms: Animals; Arsenites/toxicity*; Calcineurin/metabolism; Female; Gene Expression Regulation; HEK293 Cells; Humans; Hypertrophy, Left Ventricular/chemically induced*; Hypertrophy, Left Ventricular/metabolism; Hypertrophy, Left Ventricular/pathology; Hypertrophy, Left Ventricular/physiopathology; Isolated Heart Preparation; Male; Mice, Inbred C57BL; Myocytes, Cardiac/drug effects*; Myocytes, Cardiac/metabolism; Myocytes, Cardiac/pathology; NFATC Transcription Factors/metabolism; Sex Factors; Signal Transduction; Sodium Compounds/toxicity*; Time Factors; Ventricular Function, Left/drug effects*; Ventricular Remodeling/drug effects*; Water Pollutants, Chemical/toxicity*