Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Morris Karmazyn

Abstract

Leptin has been shown to upregulate the fat mass and obesity-associated protein (FTO) in the cardiomyocyte, an effect that has been linked to cardiomyocyte hypertrophy. In this current study, we sought to determine if other cardiomyocyte hypertrophic agonists could upregulate FTO. Angiotensin II displayed the ability to significantly upregulate mRNA expression and protein expression of FTO. Thus, in this study, we explored the cellular mechanisms behind angiotensin II-induced FTO upregulation.

Angiotensin II-induced FTO upregulation was attenuated by 10 µM valsartan, an AT-1 receptor antagonist, 5 µM EMD87580, a sodium-hydrogen exchanger isoform 1 (NHE-1) inhibitor, and 2 nM FK506, a calcineurin inhibitor. This data suggests that angiotensin II-induced FTO upregulation is AT-1 receptor mediated and has a signal transduction pathway involving the NHE-1/calcineurin system. All the above agents also abolished angiotensin II-induced hypertrophy.

In addition, our studies show that a super-ovine leptin receptor antagonist (LRA; 100 nM) and JAK2 inhibitor, 50 µM AG490, also attenuate angiotensin II-induced FTO upregulation. These results implicate the leptin-JAK2-STAT3 signalling system in angiotensin II-induced FTO upregulation. The above agents also abolished angiotensin II-induced hypertrophy.

The data suggests that NHE-1/calcineurin as well as leptin-mediated JAK2/STAT3 signalling play a critical role in angiotensin II-induced FTO upregulation.


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