Journal
CARDIOVASCULAR RESEARCH
Volume 88, Issue 1, Pages 196-204Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvq152
Keywords
Vascular diseases; Glycolysis; Warburg effect; Hypoxia-inducible factor-1; Apoptosis; Hexokinase
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [MOP-49609]
- Heart and Stroke Foundation of Canada
- Canada Research Chair
- CIHR New Investigator Award
- La Societe Quebecoise d'Hypertension Arterielle (SQHA)
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Vascular remodelling diseases are characterized by the presence of proliferative and apoptosis-resistant vascular smooth muscle cells (VSMC). There is evidence that pro-proliferative and anti-apoptotic states are characterized by metabolic remodelling (a glycolytic phenotype with hyperpolarized mitochondria) involving Akt pathway activation by circulating growth factors. Hypoxia-inducible factor-1 (HIF-1) is involved in different vascular diseases. Since this transcription factor is implicated in metabolic responses, we hypothesized that HIF-1 activity could be involved in vascular remodelling in response to arterial injury. Our findings indicate that growth factors, such as platelet-derived growth factor (PDGF), activate the Akt pathway (measured by immunoblot) in human carotid artery VSMC. Activation of this pathway increased HIF-1 activation (measured by immunoblot), leading to increased glycolysis in VSMC. Expression and mitochondrial activity of hexokinase 2 (HXK2), a primary initiator of glycolysis, are increased during HIF-1 activation. The mitochondrial activity of HXK2 in VSMC led to the hyperpolarization of mitochondrial membrane potential (measured by tetramethylrhodamine methyl-ester perchlorate) and the suppression of apoptosis (measured by TUNEL assay and 3 activity), effects that are blocked by HIF-1 inhibition. Additionally, HIF-1 inhibition also decreased VSMC proliferation (proliferating cell nuclear antigen and Ki-67 assays). In vivo, we demonstrate that localized HIF-1 inhibition, using a dominant-negative HIF-1 alpha adenoviral construct, prevented carotid artery post-injury remodelling in rats. We propose that HIF-1 is centrally involved in carotid artery remodelling in response to arterial injury and that localized inhibition of HIF-1 may be a novel therapeutic strategy to prevent carotid stenosis.
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