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

Zhao, You Yang; Zhao, Yidan; Mirza, M. B.; Huang, Julia; Potula, Hari Hara; Vogel, Steven M.; Brovkovych, Viktor; Yuan, Jason X.‐J.; Wharton, John; Malik, Asrar B.

doi:10.1172/jci33338

Cited by 258 publications

(324 citation statements)

References 61 publications

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“…Interestingly, double knockout mice (caveolin-1 and eNOS) do not develop PH. The eNOS transgenic mice with increased endothelial eNOS expression, however, do not develop PH and are protected from hypoxia-induced PH (96,132,137). These studies indicate that caveolin-1 is essential not only for inhibiting proliferative pathways but also for maintaining physiological function of eNOS.…”

Section: Disruption Of Ec Membranementioning

confidence: 84%

“…Reexpression of endothelial caveolin-1 restores vascular and cardiac pathology and dysfunction. Interestingly, increased caveolin-1 has been shown to prevent eNOS-derived ROS by forming a complex with free eNOS (62,90,137). Furthermore, inhibition of eNOS by N G -nitro-L-arginine methyl ester prevents vascular remodeling and PH in caveolin-1 Ϫ/Ϫ mice.…”

Section: Disruption Of Ec Membranementioning

confidence: 99%

“…Similarly, Berger et al (10) have reported increased expression of eNOS and inducible NO synthase in plexiform lesions in PAH associated with CHD. Zhao et al (137) using Western blot analysis showed reduced caveolin-1 expression in the lung tissue from patients with idiopathic PAH associated with normal eNOS expression and increased PKG-1 nitration. They further showed that the inhibition of eNOS or treatment with superoxide dismutase mimetic significantly attenuated PH in caveolin-1 Ϫ/Ϫ mice.…”

Section: H20 Pulmonary Hypertension and Caveolin-1mentioning

confidence: 99%

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Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Mathew R. Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity. Am J Physiol Heart Circ Physiol 306: H15-H25, 2014. First published October 25, 2013 doi:10.1152/ajpheart.00266.2013.-Pulmonary hypertension (PH) is a progressive disease with a high morbidity and mortality rate. Despite important advances in the field, the precise mechanisms leading to PH are not yet understood. Main features of PH are loss of vasodilatory response, the activation of proliferative and antiapoptotic pathways leading to pulmonary vascular remodeling and obstruction, elevated pressure and right ventricular hypertrophy, resulting in right ventricular failure and death. Experimental studies suggest that endothelial dysfunction may be the key underlying feature in PH. Caveolin-1, a major protein constituent of caveolae, interacts with several signaling molecules including the ones implicated in PH and modulates them. Disruption and progressive loss of endothelial caveolin-1 with reciprocal activation of proliferative pathways occur before the onset of PH, and the rescue of caveolin-1 inhibits proliferative pathways and attenuates PH. Extensive endothelial damage/loss occurs during the progression of the disease with subsequent enhanced expression of caveolin-1 in smooth muscle cells. This caveolin-1 in smooth muscle cells switches from being an antiproliferative factor to a proproliferative one and participates in cell proliferation and cell migration, possibly leading to irreversible PH. In contrast, the disruption of endothelial caveolin-1 is not observed in the hypoxia-induced PH, a reversible form of PH. However, proliferative pathways are activated in this model, indicating caveolin-1 dysfunction. Thus disruption or dysfunction of endothelial caveolin-1 leads to PH, and the status of caveolin-1 may determine the reversibility versus irreversibility of PH. This article reviews the role of caveolin-1 and cell membrane integrity in the pathogenesis and progression of PH.caveolin-1; endothelial cells; pulmonary hypertension; smooth muscle cells THIS ARTICLE is part of a collection on Pathophysiology of Hypertension. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.In 1891, Ernst von Romberg, a German physician, described histological changes in pulmonary hypertension (PH) as pulmonary vascular sclerosis (30). Since then remarkable advances have been made in the understanding of PH, but the pathogenesis of PH still remains elusive, partly because a number of diseases can lead to PH and multiple signaling pathways are implicated in PH. Furthermore, not all signaling pathways are activated in a given patient, and their activation may depend on the stage of the disease. Experimental data suggest that the vascular changes occur before the onset of PH (47,48). Therefore, it is not surprising that by the time the diagnosis of PH is made, most patients have significant pathological changes in pulmonary vasculatu...

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Section: Disruption Of Ec Membranementioning

confidence: 84%

Section: Disruption Of Ec Membranementioning

confidence: 99%

Section: H20 Pulmonary Hypertension and Caveolin-1mentioning

confidence: 99%

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Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Mathew

2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Functional connections between caveolin (cav) and oxidative stress have emerged in several recent studies. The loss of caveolin-1 (cav-1) increases NO and/or reactive oxygen species (ROS) production [12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

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“…However, it has been shown that Cav1 -/-mice develop PH (greater than 80% increase of pulmonary arterial pressure) [22]. These mice exhibit right ventricle hypertrophy associated with marked increase of right ventricular contractility and diastolic function [22] and increased pulmonary vascular resistance as well as pulmonary vascular remodeling evident by increased medial thickness and muscularization of distal pulmonary vessels [23]. Studies have also shown decreased pulmonary artery density and defective pulmonary artery filling [24].…”

Section: Genetic Deletion Of Cav1 Induces Ph In Micementioning

confidence: 99%

Caveolin-1 Deficiency Signaling Novel Mechanisms of Pulmonary Hypertension

Zhao¹

2012

Transl Med

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Pulmonary hypertension is an unremitting disease characterized by progressive increase of pulmonary vascular resistance and vascular remodeling. Due to poor understanding of the molecular basis of the pathogenesis, there are currently limited options available for the treatment of this devastating disease. Recent studies with Cav1 -/-mice and other genetically modified animal models as well as experimental animal models of pulmonary hypertension have demonstrated the critical role of Caveolin-1 deficiency in the pathogenesis of pulmonary hypertension. Here, we will review the current knowledge about the role of Caveolin-1 signaling in the mechanisms of pulmonary hypertension focusing on protein kinase G nitration and STAT3 activation and provide insights into the molecular basis of the pathogenesis of human pulmonary hypertension.

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

Cited by 258 publications

References 61 publications

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

Caveolin-1 Deficiency Signaling Novel Mechanisms of Pulmonary Hypertension

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