Caveolin-1 (cav-1) has been shown to play a significant role in the pathogenesis of pulmonary hypertension (PH). In the monocrotaline model of PH, the loss of endothelial cav-1 as well as reciprocal ...activation of proliferative and anti-apoptotic pathways initiate the disease process and facilitate its progression. In order to examine the role of cav-1 in hypoxia-induced PH, we exposed rats and neonatal calves to hypobaric hypoxia and obtained hemodynamic data and assessed the expression of cav-1 and related proteins eNOS, HSP90, PTEN, gp130, PY-STAT3, β-catenin, and Glut1 in the lung tissue. Chronic hypoxic exposure in rats (48 h–4 weeks) and calves (2 weeks) did not alter the expression of cav-1, HSP90, or eNOS. PTEN expression was significantly decreased accompanied by PY-STAT3 activation and increased expression of gp130, Glut1, and β-catenin in hypoxic animals. We also examined cav-1 expression in the lung sections from steers with chronic hypoxic disease (Brisket disease) and from patients with chronic lung disease who underwent lung biopsy for medical reasons. There was no cav-1 loss in Brisket disease. In chronic lung disease cases, endothelial cav-1 expression was present, albeit with less intense staining in some cases. In conclusion, hypoxia did not alter the cav-1 expression in experimental models. The presence of cav-1, however, did not suppress hypoxia-induced activation of PY-STAT3 and β catenin, increased gp130 and Glut1 expression, or prevent the PTEN loss, indicating cav-1 dysfunction in hypoxia-induced PH.
Pulmonary hypertension(PH),a serious disorder with a high morbidity and mortality rate,is known to occur in a number of unrelated systemic diseases.Several hematological disorders such as sickle cell ...disease,thalassemia and myeloproliferative diseases develop PH which worsens the prognosis.Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction.Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity,activation of proliferative and antiapoptotic pathways leading to vascular remodeling,elevated pulmonary artery pressure,right ventricular hypertrophy and premature death.Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide(NO),limiting its bioavailability,and leading to endothelial dysfunction.In addition,hemolysis releases arginase into the circulation which converts L-arginine to ornithine,thus bypassing NO production.Furthermore,treatments for hematological disorders such as immunosuppressive therapy,splenectomy,bone marrow transplantation,and radiation have been shown to contribute to the development of PH.Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension(PAH).Several studies have reported low iron levels in patients with idiopathic PAH,and iron deficiency is an important risk factor.This article reviews PH associated with hematological disorders and its mechanism:and iron homeostasis and its relevance to PH.
Reduced bone morphogenetic protein (BMP) receptor (BMPR) expression and BMP signaling have been implicated in vascular cell proliferation and remodeling associated with pulmonary arterial ...hypertension (PAH). The low penetrance of the BMPR II disease gene in familial PAH suggests that additional genetic or environmental factors are involved in clinical manifestation of PAH. Smurf1 ubiquitin ligase, together with inhibitory SMAD 6/7, forms a negative feedback loop for the attenuation of BMP signals by downregulating BMPR and signaling molecules and, in addition, functions in the integration of MAPK/Ras mitogenic pathways. The present study found that Smurf1 was significantly elevated in pulmonary arteries of monocrotaline and hypoxia-induced PAH rats. In the pulmonary artery of hypoxia-exposed mice, elevation of Smurf1 and SMAD7 was correlated with reduced expression of BMPR II protein. Over-expression of Smurf1 in cultured cells induced ubiquitination and degradation of BMPR I and II whereas ligase-inactive Smurf1 reduced ubiquitination and elevated their protein levels, thus serving a dominant-negative function. Smurf1-induced receptor degradation was inhibited by both proteasomal and lysosomal inhibitors. Thus, Smurf1 reduces steady-state levels of BMPRs by ubiquitination and subsequent degradation involving proteasomes and lysosomes. Therefore, these results show that Smurf1 induction could be a key event for triggering downregulation of BMP signaling and causing vascular cell proliferation and remodeling in PAH and that abrogating Smurf1 function could be a strategy for PAH therapeutics.
Departments of 1 Pediatrics, 2 Physiology, 3 Pathology, and 4 Medicine, New York Medical College, Valhalla, New York
Submitted 20 February 2007
; accepted in final form 1 April 2008
Monocrotaline ...(MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1, and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF- B have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation, and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC; starting on days 1 , 3 , and 14 x 2 wk), an inhibitor of inflammation and NF- B activation. Hemodynamic data, the expression of inhibitory (I)- B , caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF- B, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wk post-MCT. There was progressive reduction in the expression of caveolin-1, Tie2, and activation of PY-STAT3 in the lungs. Reduction in I- B expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF- B activation were observed only at 2 wk post-MCT and both decreased by 4 wk post-MCT despite progressive PAH. PDTC (starting on days 1 and 3 ) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I- B expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF- B activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF- B activation appear to be a transient phenomenon in the MCT model. Thus the disruption of endothelial cell membrane integrity resulting in caveolin-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.
caveolin-1; inhibitory B ; inflammation; PY-STAT3; Tie2
Address for reprint requests and other correspondence: R. Mathew, Section of Pediatric Cardiology, Munger Pavilion, New York Medical College, Valhalla, NY 10595 (e-mail: rajamma_mathew{at}nymc.edu )
Abstract
Pulmonary agenesis is a rare congenital disorder with large variability in presentation and prognosis. We describe a full-term infant born with right-sided pulmonary agenesis who underwent ...thoracoscopic placement of a tissue expander. He ultimately died of pulmonary hypertension. Immunohistology showed intimal hyperplasia without the loss of endothelial caveolin-1 expression. A literature review revealed that while some of these patients have favorable outcome, many succumb despite therapy.
AIM: To study the genesis of neointima formation in pulmonary hypertension(PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given ...monocrotaline(M, 40 mg/kg) or subjected to hypobaric hypoxia(H) to induce PH. Another group was given M and subjected to H to accelerate the disease process(M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor(PPAR) γ, caveolin-2, proliferative and antiapoptotic factors(PY-STAT3, p-Erk, Bcl-x L), endothelial nitric oxide synthase(e NOS) and heat shock protein(HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells(SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in e NOS and HSP90 expression was present in the M groups(2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP 90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.
Endothelial caveolin-1 loss is an important feature of pulmonary hypertension (PH); the rescue of caveolin-1 abrogates experimental PH. Recent studies in human PH suggest that the endothelial ...caveolin-1 loss is followed by an enhanced expression of caveolin-1 in smooth muscle cells (SMC) with subsequent neointima formation. In order to evaluate caveolin-1 expression in infants with PH, we examined the available clinical histories, hemodynamic data, and the expression of caveolin-1, PECAM-1, vWF, and smooth muscle α-actin in the lung biopsy/autopsy specimens obtained from infants with congenital heart disease (CHD, n = 8) and lung disease (n = 9). In CHD group, PH associated with increased pulmonary blood flow exhibited loss of endothelial caveolin-1 and PECAM-1 in pulmonary arteries; additional vWF loss was associated with enhanced expression of caveolin-1 in SMC. In the absence of PH, increased or decreased pulmonary blood flow did not disrupt endothelial caveolin-1, PECAM-1, or vWF; nor was there any enhanced expression of caveolin-1 in SMC. In Lung Disease + PH group, caveolin-1, PECAM-1, and vWF were well preserved in seven infants, and importantly, SMC in these arteries did not exhibit enhanced caveolin-1 expression. Two infants with associated inflammatory disease exhibited loss of endothelial caveolin-1 and PECAM-1; additional loss of vWF was accompanied by enhanced expression of caveolin-1 in SMC. Thus, associated flow-induced shear stress or inflammation, but not elevated pulmonary artery pressure alone, disrupts endothelial caveolin-1. Subsequent vWF loss, indicative of extensive endothelial damage is associated with enhanced expression of caveolin-1 in SMC, which may worsen the disease.
PDF
