期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 14, 页码 E841-E850出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1202081109
关键词
aortic root dilatation; congestive heart failure; endothelium
资金
- National Institutes of Health [P01-HL65608, N01-HV28180, HHS-N268201000032C]
- Johns Hopkins Institute for Cell Engineering
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-1 alpha 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-1 alpha expression only in Tie(2+) 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-beta 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-beta signaling in Hif1a(f/f); Tie2-Cre mice. Inhibition of TGF-beta 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-beta signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1 alpha 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.
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