Disruption of caveolin-1 leads to enhanced nitrosative stress and severe systolic and diastolic heart failure

Wunderlich, Carsten; Schober, Kristin; Lange, Stefan; Drab, Marek; Braun-Dullaeus, Ruediger C.; Kasper, Michael; Schwencke, Carsten; Schmeißer, Alexander; Strasser, Ruth H.

doi:10.1016/j.bbrc.2005.12.058

Cited by 64 publications

(66 citation statements)

References 22 publications

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“…Other potentially important sequelae of cav-1 deletion may include altered regulation of apoptosis and inflammation as suggested by other recent studies (20,22). These additional functions of cav-1 may be relevant since pulmonary hypertension is associated with endothelial cell-specific apoptosis and considerable vascular inflammation.…”

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confidence: 78%

“…Cav-1 Ϫ/Ϫ mice display increased eNOS expression in cardiac tissue, increased eNOS activity in aortic rings and responsiveness to acetylcholine-induced relaxation, increased systemic nitric oxide (NO) production, as well as increased NO release from vascular smooth muscle cells derived from these animals (2, 4, 17). The increased NO bioavailability for vascular processes has also been associated with increased nitrosative stress in these animals, as evidenced by increased nitrotyrosine formation in cardiac tissue (22). Further evidence of deregulated signaling pathways were evident by increased p42/44 MAPK (ERK1/2) activation in cardiac fibroblasts from cav-1 Ϫ/Ϫ mice as well as increased Akt activation in lung vasculature, which promote the cardiac and pulmonary hypercellularity (2,12).…”

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confidence: 99%

“…Furthermore, cav-1 Ϫ/Ϫ mice exhibit insulin resistance and hyperproliferation of adipose tissue (3). Significant cardiac defects were observed in cav-1 Ϫ/Ϫ mice including increased right ventricular volume and hypertrophy, left ventricular wall thickening, loss of systolic function, and evidence of cardiac fibrosis (2,4,22). The lungs of cav-1 Ϫ/Ϫ mice display a thickening of the parenchyma and alveolar septae resulting from bronchial and alveolar epithelial cell hyperproliferation (12,17), evidence of endothelial cell proliferation (17), and pulmonary fibrosis (4).…”

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confidence: 99%

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Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

Ryter

Choi

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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CAVEOLAE ARE 50-to 100-nm -shaped invaginations of the cell surface plasma membrane enriched in glycosphingolipids and cholesterol that occur in a variety of cell types including epithelial and endothelial cells, fibroblasts, smooth muscle cells, and adipocytes (1). These structures facilitate endocytosis of particles and participate in vesicular trafficking. Caveolin-1 (cav-1), a 21-to 24-kDa protein, is the major resident scaffolding protein constituent of caveolae (1). In addition to providing the structural integrity of caveolae, cav-1 exerts major regulatory functions on intracellular signaling pathways, in particular, those that originate at the plasma membrane. Cav-1 can form complexes with many signaling-associated proteins that reside in the caveolae, resulting in the modulation and usually inhibition of corresponding enzymatic activities. Among these are the endothelial (constitutive) nitric oxide synthase (eNOS; Ref. 5), heme oxygenase-1 (9), phosphatidylinositol 3-kinase, GTPases, estrogen receptors, the EGF and PDGF receptors, and others (1, 16).The profound involvement of cav-1 in cellular and tissue homeostasis is evident by the aberrant pulmonary and vascular phenotypes observed in cav-1 (cav-1 Ϫ/Ϫ ) animals, among which include hypercellularity in the lungs and heart (2, 4, 17-18). Although cav-1 Ϫ/Ϫ mice are viable, they display a dramatically shortened life span and a distinct loss of caveolae structures (4, 13). Furthermore, cav-1 Ϫ/Ϫ mice exhibit insulin resistance and hyperproliferation of adipose tissue (3). Significant cardiac defects were observed in cav-1 Ϫ/Ϫ mice including increased right ventricular volume and hypertrophy, left ventricular wall thickening, loss of systolic function, and evidence of cardiac fibrosis (2,4,22). The lungs of cav-1 Ϫ/Ϫ mice display a thickening of the parenchyma and alveolar septae resulting from bronchial and alveolar epithelial cell hyperproliferation (12, 17), evidence of endothelial cell proliferation (17), and pulmonary fibrosis (4).Despite systemic hypotension, cav-1 Ϫ/Ϫ animals develop significant pulmonary hypertension and associated increases in pulmonary artery pressure and right ventricular hypertrophy as described in this issue of AJP-Lung by Maniatis et al. (11) and by others (4, 17,23). Endothelial cell-specific reconstitution of cav-1 expression in cav-1 Ϫ/Ϫ mice restored the pulmonary and vascular defects observed in these animals, as evident by the reversal of the pulmonary hypertension and cardiac hypertrophy (12). Alveolar hypercellularity was also partially compensated by cav-1 reconstitution, which inhibited the endothelial cell proliferation (12). These studies illustrate a major role for endothelium-expressed cav-1 in vascular homeostasis, although the importance of this molecule is not limited to endothelial cells.Extensive experimentation with cav-1 Ϫ/Ϫ mice has revealed the critical role of cav-1 in the regulation of signaling processes. Cav-1 Ϫ/Ϫ mice display increased eNOS expression in cardiac tissue, increased eNOS activity i...

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confidence: 99%

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confidence: 99%

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Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

Ryter

Choi

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In the endothelium, Cav-1 anchors eNOS to caveolae, thus preventing its activation and reducing NO production and vascular relaxation (3,7,33). Previous studies have used Cav-1 KO mice on normal rodent chow (ϳ0.8% NaCl) to examine the role of Cav-1 in mechanotransduction, vascular remodeling, and cardiovascular function (5,29,41,42). In one study, Cav-1 null mice showed evidence of hyper-proliferative and vascular abnormalities (29).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence also suggests a role of Cav-1 in the anchoring of endothelial NO synthase (eNOS) to caveolae, thus limiting its translocation and phosphoactivation (3,7,33). These studies have suggested a role of Cav-1 in the regulation of vascular function and growth (5,29,42), as well as in the normal systolic and diastolic cardiac function (41).…”

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Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Pojoga

Yao²,

Sinha³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol 294: H1258-H1265, 2008. First published January 4, 2008 doi:10.1152/ajpheart.01014.2007.-Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1 Ϫ/Ϫ ) and wild-type control mice (WT; Cav-1 ϩ/ϩ ) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with N G -nitro-L-arginine methyl ester and more so in Cav-1 Ϫ/Ϫ than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1 Ϫ/Ϫ (maximum 0.25 Ϯ 0.06 g/mg) compared with WT (0.75 Ϯ 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1 Ϫ/Ϫ (0.27 Ϯ 0.05 g/mg) compared with WT mice (0.53 Ϯ 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10 Ϫ5 M) caused aortic relaxation in WT mice on HS (23.6 Ϯ 3.5%) and LS (23.7 Ϯ 5.5%) that was enhanced in Cav-1 Ϫ/Ϫ HS (72.6 Ϯ 6.1%) and more so in Cav-1 Ϫ/Ϫ LS mice (93.6 Ϯ 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1 Ϫ/Ϫ compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake. endothelium; nitric oxide; vascular smooth muscle; blood pressure; hypertension HIGH-SALT (HS) DIET IS OFTEN associated with increased vascular volume (4, 15). The volume overload triggers suppression of the renin-angiotensin-aldosterone system, leading to increased salt and water excretion and restoration of v...

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Imbalance of Caveolin‐1 and eNOS Expression in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

Hofmann

Gosemann

Takahashi

et al. 2014

Birth Defects Research Pt B

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Disruption of caveolin-1 leads to enhanced nitrosative stress and severe systolic and diastolic heart failure

Cited by 64 publications

References 22 publications

Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

Caveolin-1: a critical regulator of pulmonary vascular architecture and nitric oxide bioavailability in pulmonary hypertension

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Imbalance of Caveolin‐1 and eNOS Expression in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

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