Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration

You Yang Zhao, Yidan D. Zhao, Muhammad K. Mirza, Julia H. Huang, Hari Hara S K Potula, Steven M. Vogel, Viktor Brovkovych, Jason Yuan, John Wharton, Asrar B. Malik

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

Pulmonary hypertension (PH) is an unremitting disease defined by a progressive increase in pulmonary vascular resistance leading to right-sided heart failure. Using mice with genetic deletions of caveolin 1 (Cav1) and eNOS (Nos3), we demonstrate here that chronic eNOS activation secondary to loss of caveolin-1 can lead to PH. Consistent with a role for eNOS in the pathogenesis of PH, the pulmonary vascular remodeling and PH phenotype of Cav1-/- mice were absent in Cav1-/-Nos3-/- mice. Further, treatment of Cav1-/- mice with either MnTMPyP (a superoxide scavenger) or L-NAME (a NOS inhibitor) reversed their pulmonary vascular pathology and PH phenotype. Activation of eNOS in Cav1-/- lungs led to the impairment of PKG activity through tyrosine nitration. Moreover, the PH phenotype in Cav1-/- lungs could be rescued by overexpression of PKG-1. The clinical relevance of the data was indicated by the observation that lung tissue from patients with idiopathic pulmonary arterial hypertension demonstrated increased eNOS activation and PKG nitration and reduced caveolin-1 expression. Together, these data show that loss of caveolin-1 leads to hyperactive eNOS and subsequent tyrosine nitration-dependent impairment of PKG activity, which results in PH. Thus, targeting of PKG nitration represents a potential novel therapeutic strategy for the treatment of PH.

Original languageEnglish (US)
Pages (from-to)2009-2018
Number of pages10
JournalJournal of Clinical Investigation
Volume119
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

Fingerprint

Caveolin 1
Pulmonary Hypertension
Lung
Phenotype
Tyrosine
NG-Nitroarginine Methyl Ester
Superoxides
Vascular Resistance
Blood Vessels
Therapeutics
Heart Failure
Pathology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhao, Y. Y., Zhao, Y. D., Mirza, M. K., Huang, J. H., Potula, H. H. S. K., Vogel, S. M., ... Malik, A. B. (2009). Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. Journal of Clinical Investigation, 119(7), 2009-2018. https://doi.org/10.1172/JCI33338

Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. / Zhao, You Yang; Zhao, Yidan D.; Mirza, Muhammad K.; Huang, Julia H.; Potula, Hari Hara S K; Vogel, Steven M.; Brovkovych, Viktor; Yuan, Jason; Wharton, John; Malik, Asrar B.

In: Journal of Clinical Investigation, Vol. 119, No. 7, 01.07.2009, p. 2009-2018.

Research output: Contribution to journalArticle

Zhao, YY, Zhao, YD, Mirza, MK, Huang, JH, Potula, HHSK, Vogel, SM, Brovkovych, V, Yuan, J, Wharton, J & Malik, AB 2009, 'Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration', Journal of Clinical Investigation, vol. 119, no. 7, pp. 2009-2018. https://doi.org/10.1172/JCI33338
Zhao, You Yang ; Zhao, Yidan D. ; Mirza, Muhammad K. ; Huang, Julia H. ; Potula, Hari Hara S K ; Vogel, Steven M. ; Brovkovych, Viktor ; Yuan, Jason ; Wharton, John ; Malik, Asrar B. / Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 7. pp. 2009-2018.
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