Hypoxia inducible factor-1 improves the negative functional effects of natriuretic peptide and nitric oxide signaling in hypertrophic cardiac myocytes

• Published in: Life sciences (1973) Vol. 87; no. 1; pp. 9 - 16
• Main Authors: Tan, Tao, Scholz, Peter M., Weiss, Harvey R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 03.07.2010
• Subjects: Animals; Carbazoles - administration & dosage; Cardiac hypertrophy; Cardiomegaly - physiopathology; Cyclic GMP; Cyclic GMP - metabolism; Cyclic GMP-dependent protein kinase; Cyclic GMP-Dependent Protein Kinases - metabolism; Deferoxamine - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxic inducible factor-1 (HIF-1); Male; Mice; Mice, Inbred C57BL; Myocytes; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Natriuretic Peptide, Brain - administration & dosage; Natriuretic Peptide, Brain - metabolism; Natriuretic Peptide, C-Type - administration & dosage; Natriuretic Peptide, C-Type - metabolism; Natriuretic peptides; Nitric oxide; Nitric Oxide - metabolism; S-Nitroso-N-Acetylpenicillamine - pharmacology; Signal Transduction; Up-Regulation; Cyclic GMP; Nitric oxide; Cardiac hypertrophy; Myocytes; Cyclic GMP-dependent protein kinase; Hypoxic inducible factor-1 (HIF-1); Natriuretic peptides
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2010.05.002

Both natriuretic peptides and nitric oxide may be protective in cardiac hypertrophy, although their functional effects are diminished in hypertrophy. Hypoxia inducible factor-1 (HIF-1) may also protect in cardiac hypertrophy. We hypothesized that upregulation of HIF-1 would protect the functional effects of cyclic GMP (cGMP) signaling in hypertrophied ventricular myocytes. A cardiac hypertrophy model was created in mice by transverse aorta constriction. HIF-1 was increased by deferoxamine (150 mg/kg for 2 days). HIF-1α protein levels were examined. Functional parameters were measured (edge detector) on freshly isolated myocytes at baseline and after BNP (brain natriuretic peptide, 10 − 8 –10 − 7 M) or CNP (C-type natriuretic peptide, 10 − 8 –10 − 7 M) or SNAP (S-nitroso-N-acetyl-penicillamine, a nitric oxide donor, 10 − 6 –10 − 5 M) followed by KT5823 (a cyclic GMP-dependent protein kinase (PKG) inhibitor, 10 − 6 M). We also determined PKG expression levels and kinase activity. We found that under control conditions, BNP (− 24%), CNP (− 22%) and SNAP (− 23%) reduced myocyte shortening, while KT5823 partially restored function. Deferoxamine treated control myocytes responded similarly. Baseline function was reduced in the myocytes from hypertrophied heart. BNP, CNP, SNAP and KT5823 also had no significant effects on function in these myocytes. Deferoxamine restored the negative functional effects of BNP (− 22%), CNP (− 18%) and SNAP (− 19%) in hypertrophic cardiac myocytes and KT5823 partially reversed this effect. Additionally, deferoxamine maintained PKG expression levels and activity in hypertrophied heart. Our results indicated that the HIF-1 protected the functional effects of cGMP signaling in cardiac hypertrophy through preservation of PKG.