Abstract
Myocardial ischemia–reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha). While previous studies implicate HIF1-alpha in cardioprotection, the role of HIF2-alpha remains elusive. Here we show that HIF2-alpha induces the epithelial growth factor amphiregulin (AREG) to elicit cardioprotection in myocardial IRI. Comparing mice with inducible deletion of Hif1a or Hif2a in cardiac myocytes, we show that loss of Hif2-alpha increases infarct sizes. Microarray studies in genetic models or cultured human cardiac myocytes implicate HIF2-alpha in the myocardial induction of AREG. Likewise, AREG increases in myocardial tissues from patients with ischemic heart disease. Areg deficiency increases myocardial IRI, as does pharmacologic inhibition of Areg signaling. In contrast, treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion. These studies indicate that HIF2-alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance.
Highlights
Myocardial ischemia–reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha)
Based on previous studies implicating hypoxia-inducible transcription factors (HIFs) in organ-protection during ischemia and reperfusion injury[2,7], we hypothesized that myocyte-specific HIFs dampen myocardial ischemia and reperfusion injury
To overcome the problem that mice with a global Hif1a or Hif2a deletion die during embryogenesis[20], we generated mice with induced deletion of Hif1a or Hif2a in cardiac myocytes
Summary
Myocardial ischemia–reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha). Treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion These studies indicate that HIF2-alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance. HIFs have been implicated in mediating cardioprotection provided by remote ischemic preconditioning, a cardioprotective strategy where treatment of a limb for short time periods of ischemia results in attenuated myocardial infarct sizes[5,13] Due to their high metabolic demand, the functional role of myocytes in cardio-adaptive responses during ischemia has been the focus of many studies[4,14], and several have indirectly suggested myocardial-expressed HIFs in cardioprotection[14]. Exposure of these two mouse strains to IRI revealed a previously unappreciated role in cardioprotection for myocytedependent Hif2-alpha via induction of the growth factor amphiregulin (Areg)
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