The purine nucleotide cycle: a cardioprotective pathway induced by HIF‐1α (887.4)

Abstract

Overexpression of hypoxia inducible factor 1α (HIF‐1α) confers robust ischemic cardioprotection. Previously we showed that HIF‐1α induces the ability to use fumarate as a terminal electron acceptor to sustain mitochondrial anaerobic electron transport chain (ETC) activity. The source of fumarate for ETC activity was established to be the purine nucleotide cycle (PNC). Here, we report that mRNA, protein, and activity of the rate‐limiting enzyme in the PNC, AMP deaminase, is induced by HIF‐1α. Thus, in addition to providing fumarate for anaerobic ETC activity, we hypothesized that induction of the PNC might serve as a mechanism that conserves the nucleotide pool during ischemia. The AMP that accumulates during ischemia can be metabolized by AMP deaminase to IMP, a membrane impermeable metabolite. Alternatively, AMP can be degraded to adenosine, which can diffuse into the interstitial space leading to a reduction of the cardiomyocyte's nucleotide pool. Consistent with our hypothesis, we show that HIF‐1α‐expressing hearts accumulate significantly less adenosine than wildtype hearts during ischemia. Collectively, our findings indicate that the PNC is a novel cardioprotective mechanism induced by HIF‐1α that preserves ETC activity while conserving the nucleotide pool.Grant Funding Source: Supported by NIH grant R01HL084302