A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation.
Severe pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary vascular resistance and vascular remodeling leading to right heart failure and early death. Our recent studies with the use of the novel mouse model with genetic deletions of caveolin-1 (Cav1) and endothelial nitric oxide synthase (eNOS) (NOS3) have demonstrated that persistent eNOS activation in Cav1(-/-) lungs results in tyrosine nitration of protein kinase G (PKG) and impairment of its activity, which thereby induces PH. The finding of eNOS activation and PKG nitration concomitant with Cav1 deficiency was recapitulated in lungs from patients with idiopathic pulmonary arterial hypertension. These data suggest targeting PKG nitration has potential value for the treatment of PH. Here, we will review the current knowledge about Cav1-regulated eNOS activity and its fundamental role in the pathogenesis of PH.
Zhao
You-Yang
YY
Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612, USA. yyzhao@uic.edu <yyzhao@uic.edu>
Malik
Asrar B
AB
D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D051242:Caveolin 1; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; D017869:Cyclic GMP-Dependent Protein Kinases
J Biol Chem. 1997 Jun 20;272(25):15583-6
9188442
J Biol Chem. 1997 Jul 25;272(30):18522-5
9228013
J Appl Physiol (1985). 2001 Apr;90(4):1299-306
11247927
Circulation. 2008 Jun 10;117(23):2966-8
18541751
FASEB J. 2007 Sep;21(11):2970-9
17470567
Am J Physiol Lung Cell Mol Physiol. 2008 May;294(5):L865-73
18192592
Am J Respir Crit Care Med. 2001 Sep 15;164(6):1038-42
11587993
Physiol Rev. 2004 Oct;84(4):1341-79
15383654
Nat Clin Pract Cardiovasc Med. 2007 Jun;4(6):319-29
17522721
N Engl J Med. 1997 Jan 9;336(2):111-7
8988890
J Biol Chem. 2001 Oct 12;276(41):38121-38
11457855
Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L1012-20
17616649
Circ Res. 2005 Mar 4;96(4):442-50
15692087
Circulation. 2004 Sep 14;110(11):1499-506
15353500
Hypertension. 2001 Feb;37(2):322-7
11230292
N Engl J Med. 2004 Oct 14;351(16):1655-65
15483284
J Clin Invest. 2009 Jul;119(7):2009-18
19487814
Science. 2001 Sep 28;293(5539):2449-52
11498544
Adv Exp Med Biol. 2007;618:101-12
18269191
Circulation. 2006 Aug 29;114(9):912-20
16940204
J Pathol. 1998 Jul;185(3):313-8
9771486
Nat Med. 2000 Dec;6(12):1362-7
11100121
Am J Respir Crit Care Med. 2004 Mar 15;169(6):764-9
14701708
J Cardiovasc Pharmacol. 1999 Dec;34(6):879-86
10598133
Hum Mutat. 2006 Feb;27(2):121-32
16429395
Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-4
2154753
Cell. 2001 Aug 24;106(4):403-11
11525727
Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30
16456139
Lancet. 2003 May 3;361(9368):1533-44
12737878
J Clin Invest. 1999 Mar;103(6):897-905
10079111
Nat Genet. 2000 Sep;26(1):81-4
10973254
Circ Res. 2001 Mar 30;88(6):555-62
11282888
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11375-80
12177436
Chest. 2006 Mar;129(3):696-705
16537870
J Biol Chem. 1996 Sep 13;271(37):22810-4
8798458
Pulm Pharmacol Ther. 2008;21(3):507-15
18226570
J Clin Invest. 2002 May;109(10):1287-9
12021243
Cardiovasc Res. 1997 May;34(2):268-72
9205539
Cell. 1992 Feb 21;68(4):673-82
1739974