(Verbatim from the application): HIF- 1a is a central mediator of hypoxia-induced alterations in gene transcription and is likely to play a prominent role in hypoxic signaling in cardiac myocytes. Using cre-lox based conditional gene targeting we have generated viable mice with cardiac myocyte specific homozygous deletion of HIF-l a. Our initial findings have documented changes in cardiac morphotnetry, diastolic function, expression of glucose transporters, and responses to physiologic cardiac stress in these mice. These findings establish that homozygous deletion of HIF-1alpha in cardiac myocytes is not fully compensated by complimentary hypoxic signaling mechanisms. These mice present a unique and powerful model system to study the role of hypoxic signaling in cardiac adaptive responses to hypoxia/ischemia and hemodynamic stress. We will use these mice to study the role of HIF-1alpha in cardiac glucose metabolism, contractile function, angiogenesis, and adaptation to pressure overload and chronic hypoxia. We have also developed adenovirus vectors that force overexpression of HIF-la. We have shown these vectors capable of transcriptionally activating HIF1alpha responsive genes, and have discovered that augmented HIF-1alpha signaling results in a decrease of SERCA2 transcripts; a finding that may have implications regarding the effects of hypoxia/ischemia on cardiac contractile function. In this proposal we will further delineate the specific role of HIF-1alpha dependent signaling in the cardiac myocyte and fulfill the following aims: 1) Determine the role of cardiac myocyte specific HIF-1alpha dependent signaling in metabolic, morphometric and functional adaptation to hypoxia and pressure overload. 2) Determine the role of cardiac myocyte specific HIF-1alpha dependent signaling in paracrine mediation of angiogenesis in adaptation to hypoxia and pressure overload. 3) Determine the role of cardiac myocyte specific HIF-1alpha dependent signaling in myocyte survival and apoptosis pathways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064001-04
Application #
6683198
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Goldman, Stephen
Project Start
2000-12-15
Project End
2004-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$278,740
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Liu, Dinggang; Lei, Li; Desir, Matthew et al. (2016) Smooth Muscle Hypoxia-Inducible Factor 1? Links Intravascular Pressure and Atherosclerosis--Brief Report. Arterioscler Thromb Vasc Biol 36:442-5
Huang, Yan; Di Lorenzo, Annarita; Jiang, Weidong et al. (2013) Hypoxia-inducible factor-1? in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-?-angiotensin II receptor type 1 axis. Hypertension 62:634-40
Zhang, H Steve; Liu, Dingang; Huang, Yan et al. (2012) A designed zinc-finger transcriptional repressor of phospholamban improves function of the failing heart. Mol Ther 20:1508-15
Lei, Li; Liu, Dinggang; Huang, Yan et al. (2008) Endothelial expression of beta1 integrin is required for embryonic vascular patterning and postnatal vascular remodeling. Mol Cell Biol 28:794-802
Giordano, Frank J (2007) Therapeutic gene regulation: targeting transcription. Circulation 115:1180-3
Yu, Jun; Lei, Li; Liang, Yuxin et al. (2006) An engineered VEGF-activating zinc finger protein transcription factor improves blood flow and limb salvage in advanced-age mice. FASEB J 20:479-81
Abbott, J Dawn; Huang, Yan; Liu, Dingang et al. (2004) Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110:3300-5
Huang, Yan; Hickey, Reed P; Yeh, Jennifer L et al. (2004) Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J 18:1138-40
Rebar, Edward J; Huang, Yan; Hickey, Reed et al. (2002) Induction of angiogenesis in a mouse model using engineered transcription factors. Nat Med 8:1427-32