Inhibition of Phosphatidylinositol 3-kinase/Akt Signaling Attenuates Hypoxia-induced Pulmonary Artery Remodeling and Suppresses CREB Depletion in Arterial Smooth Muscle Cells

被引:73
作者
Garat, Chrystelle V. [1 ,2 ]
Crossno, Joseph T., Jr. [1 ,2 ]
Sullivan, Timothy M. [1 ]
Reusch, Jane E. B. [1 ,3 ,4 ,5 ]
Klemm, Dwight J. [1 ,2 ]
机构
[1] Univ Colorado Anschutz Med Campus, Cardiovasc Pulm Res Lab, Aurora, CO 80045 USA
[2] Univ Colorado Anschutz Med Campus, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA
[3] Univ Colorado Anschutz Med Campus, Div Endocrinol, Aurora, CO 80045 USA
[4] Vet Affairs Med Ctr, Res Serv, Denver, CO USA
[5] Vet Affairs Med Ctr, Endocrine Serv, Denver, CO USA
关键词
pulmonary arterial hypertension; CREB; hypoxia; phosphatidylinositol; 3-kinase; Akt; smooth muscle cell; IN-VIVO; GROWTH-INHIBITION; GENE-EXPRESSION; DNA-SYNTHESIS; KINASE-B; ANGIOGENESIS; PROLIFERATION; MIGRATION; HYPERTENSION; PI3K;
D O I
10.1097/FJC.0000000000000014
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase-mediated vasoconstriction.
引用
收藏
页码:539 / 548
页数:10
相关论文
共 44 条
[1]
Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle [J].
Bornfeldt, KE ;
Krebs, EG .
CELLULAR SIGNALLING, 1999, 11 (07) :465-477
[2]
The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells - Dependence on the availability of downstream targets [J].
Bornfeldt, KE ;
Campbell, JS ;
Koyama, H ;
Argast, GM ;
Leslie, CC ;
Raines, EW ;
Krebs, EG ;
Ross, R .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (04) :875-885
[3]
Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo [J].
Chen, JH ;
Somanath, PR ;
Razorenova, O ;
Chen, WS ;
Hay, N ;
Bornstein, P ;
Byzova, TV .
NATURE MEDICINE, 2005, 11 (11) :1188-1196
[4]
CLOZEL JP, 1991, J CARDIOVASC PHARM, V17, P36, DOI 10.1097/00005344-199101000-00006
[5]
INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN-MEDIATED BY PROTEIN-KINASE-B [J].
CROSS, DAE ;
ALESSI, DR ;
COHEN, P ;
ANDJELKOVICH, M ;
HEMMINGS, BA .
NATURE, 1995, 378 (6559) :785-789
[6]
Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling [J].
Crossno, Joseph T. ;
Garat, Chrystelle V. ;
Reusch, Jane E. B. ;
Morris, Kenneth G. ;
Dempsey, Edward C. ;
McMurtry, Ivan F. ;
Stenmark, Kurt R. ;
Klemm, Dwight J. .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2007, 292 (04) :L885-L897
[7]
CHARACTERIZATION OF FIBROBLAST MITOGENS AND CHEMOATTRACTANTS PRODUCED BY ENDOTHELIAL-CELLS EXPOSED TO HYPOXIA [J].
DAWES, KE ;
PEACOCK, AJ ;
GRAY, AJ ;
BISHOP, JE ;
LAURENT, GJ .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1994, 10 (05) :552-559
[8]
Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase [J].
Fagan, KA ;
Oka, M ;
Bauer, NR ;
Gebb, SA ;
Ivy, DD ;
Morris, KG ;
McMurtry, IF .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2004, 287 (04) :L656-L664
[10]
Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation [J].
Furgeson, Seth B. ;
Simpson, Peter A. ;
Park, Insun ;
VanPutten, Vicki ;
Horita, Henrick ;
Kontos, Christopher D. ;
Nemenoff, Raphael A. ;
Weiser-Evans, Mary C. M. .
CARDIOVASCULAR RESEARCH, 2010, 86 (02) :274-282