Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration
You-Yang Zhao, … , John Wharton, Asrar B. Malik
You-Yang Zhao, … , John Wharton, Asrar B. Malik
Published June 1, 2009
Citation Information: J Clin Invest. 2009;119(7):2009-2018. https://doi.org/10.1172/JCI33338.
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Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration

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.

Authors

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

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Figure 8

Tyrosine nitration–induced impairment of PKG activity mediates PH in Cav1–/– mice.

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Tyrosine nitration–induced impairment of PKG activity mediates PH in Cav...
(A) Reduced RVSP in Cav1–/– mice treated with MnTMPyP. Cav1–/– mice were treated with either MnTMPyP (5 mg/kg, i.p., daily) (Cav1-Mn) or saline (Cav1–/–) for 6 weeks. Data are expressed as mean ± SD (n = 5 per group). *P < 0.01, Cav1–/– versus WT; **P < 0.05, Cav1-Mn versus Cav1–/– ; †P > 0.05, Cav1-Mn versus WT. (B) Inhibition of NOS with l-NAME reversed PH in Cav1–/– mice. Cav1–/– mice received water ad libitum (Cav1–/–, control) or water with 1 mg/ml l-NAME (Cav-L) or its inactive analog d-NAME (Cav-D) for 5 weeks. Data are expressed as mean ± SD (n = 5–7). *P < 0.01, Cav1–/– versus WT; ‡P < 0.05, Cav-L versus Cav1–/–; §P > 0.5, Cav-D versus Cav1–/–. (C–F) Restoration of PKG-1 activity in Cav1–/– lungs reversed PH. At 7 days after administration of recombinant adenovirus expressing either human PKG-1 (AdvPKG) or LacZ, lungs were collected for Western blotting (C) and PKG kinase activity assay (D) after measurements of RVSP (E) and PVR (F). PKG activity is expressed as mean ± SD (n = 3–4). #P > 0.5 versus WT; ††P < 0.05 versus WT or Cav1–/– treated with AdvPKG (D). RVSP is expressed as mean ± SD (n = 4–5). ‡‡P < 0.05, Cav1–/–-AdvPKG (PKG) versus Cav1–/–-AdvLacZ (LacZ) (E). PVR is expressed as mean ± SD (n = 3–4). §§P < 0.05, Cav1–/–-AdvPKG versus Cav1–/–-AdvLacZ (F).