title: HIF-1α in the heart: remodeling nucleotide metabolism.
abstract: These studies have examined the effect of hypoxia inducible factor 1α (HIF-1α) on nucleotide metabolism in the ischemic heart using a genetic mouse model with heart-specific and regulated expression of a stable form of HIF-1α. We find that AMP deaminase (AMPD), the entry point of the purine nucleotide cycle (PNC), is induced by HIF-1α at the level of mRNA, protein, and activity. AMP that accumulates during ischemia can be metabolized to adenosine by 5'-nucleotidase or to IMP by AMPD. Consistent with the finding of AMPD induction, adenosine accumulation during ischemia was much attenuated in HIF-1α-expressing hearts. Further investigation of nucleotide salvage enzymes found that hypoxanthine phosphoribosyl transferase (HPRT) is also upregulated in HIF-1α-expressing hearts. Treatment of hearts with an inhibitor of the PNC, hadacidin, hastens the fall of the adenylate energy charge during ischemia and the accumulation of AMP. The results provide new insight into the role of the PNC in the heart, especially as it relates to ischemia, and indicate that HIF-1α regulates nucleotide metabolism as a compensatory response to hypoxia.
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Joe
authors: J
authors: Wu
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Cherie
authors: C
authors: Bond
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Ping
authors: P
authors: Chen
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Minghua
authors: M
authors: Chen
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Ying
authors: Y
authors: Li
authors: Department of Medicine, John Burns College of Medicine, University of Hawaii, Honolulu, HI, USA.
authors: Ralph V
authors: RV
authors: Shohet
authors: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA. Electronic address: wrightgl@mail.etsu.edu.
authors: Gary
authors: G
authors: Wright
mesh_terms: D000659:AMP Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D013997:Time Factors
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009711:Nucleotides; D000659:AMP Deaminase
keywords: Cardioprotection; Mitochondrial respiration; Nucleotide salvage; Purine nucleotide cycle