Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling

Abstract

Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O 2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O 2 homeostasis. Mouse embryos lacking expression of the O 2 -regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1a f/f ;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2 + lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1a f/f ;Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK–ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

“…Transgenic mice with HIF-1α expression driven by the α-myosin heavy chain gene promoter had reduced infarct size after coronary artery ligation compared with controls, although this effect may have been due to increased vascular density in the transgenic hearts (42). In contrast, there was no difference in vascular density in Hif1a f/f ; Tie2-Cre − compared with Hif1a f/f ; Tie2-Cre + hearts (35), indicating that differences in vascularization cannot explain the loss of IPC-induced protection in Hif1a f/f ; Tie2-Cre + hearts. The Tie2 promoter is also active in BM cells, resulting in Cre expression and loss of HIF-1 activity in myeloid and lymphoid cells of Tie2-Cre + mice (Fig.…”

Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

“…Digoxin is known as an inhibitor for HIF1a expression and blocker for number of cancer types. [37][38][39][40] Strikingly, treatment with digoxin caused a fast and specific increase in blood glucose levels specifically in KO mice (Figure 5c). Consistently, treated KO mice displayed decrease expression of HIF1a target genes, namely GLUT1 and prolyl-hydroxylase domain 3 (PHD3) (Supplementary Figure S5B), while WT mice did not show any decrease in the levels of these genes (Supplementary Figure S5C).…”

Expression and significance of HIF-1α in pulmonary fibrosis induced by paraquat

“…Rats in the control group (n ¼ 6) underwent gavage with 1 mL normal saline, while those in the PQ group (n ¼ 80) received intragastric infusion of 20% paraquat solution 50 mg/kg. Rats in PQ group were subsequently divided into 8 subgroups (10 for each subgroup) at different predetermined time points (2,6,12,24,48,72, 96 h and 7 d).…”