Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury

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.

Hippo Signaling Controls NLR Family Pyrin Domain Containing 3 Activation and Governs Immunoregulation of Mesenchymal Stem Cells in Mouse Liver Injury

“…Interestingly, the purinergic receptors induced cell proliferation and migration in injured tissues by regulating YAP activation, suggesting that there is a crosstalk between purinergic receptors and the Hippo‐YAP pathway. Moreover, the hypoxia‐inducible factors regulated their target genes, leading to resistance to ischemia and controlling excessive inflammation, which may interact with YAP under hypoxic conditions . These reports suggest that Hippo pathway–mediated immune regulation may be involved in multiple signaling pathways during sterile inflammatory injury.…”

Deduction of novel genes potentially involved in hypoxic AC16 human cardiomyocytes using next-generation sequencing and bioinformatics approaches

“…Differential gene expression with altered signaling pathways has been reported in CMs responding to hypoxic/ischemic conditions ( 3 , 29 , 30 ). The reciprocal regulation of miRNAs and…”

Luteolin modulates SERCA2a via Sp1 upregulation to attenuate myocardial ischemia/reperfusion injury in mice

“…Myocardial samples were lysed to extract protein which was subjected to SDS–polyacrylamide gel electrophoresis, and transferred to polyvinylidene fluoride membranes (Merck Millipore, Billerica, MA, USA). Western blotting was performed according to a previous protocol 57 using diluted primary antibodies against SERCA2a (1:2,000), Sp1 (1:200), Bax (1:1,000) (Santa Cruz Biotechnology, Santa Cruz, CA, USA), Bcl-2 (1:1,000) (Abcam, Cambridge, UK) and caspase 3 (1:1,000) (Cell Signaling Technology, CST, USA). Anti-mouse-HRP and anti-rabbit-HRP secondary antibodies were purchased from ZSGB-BIO (Beijing, China).…”