Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart

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

Research output: Contribution to journalArticlepeer-review


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. onsidering 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.

Original languageEnglish (US)
Pages (from-to)H1321-H1336
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number4
StatePublished - Apr 2021


  • Blood pressure
  • Cardiac hypertrophy
  • Environmental exposure
  • Inorganic arsenic exposure
  • Sex differences

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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