Caveolae are flask-shaped invaginations of cell membrane that play a significant structural and functional role. Caveolae harbor a variety of signaling molecules and serve to receive, concentrate and transmit extracel...Caveolae are flask-shaped invaginations of cell membrane that play a significant structural and functional role. Caveolae harbor a variety of signaling molecules and serve to receive, concentrate and transmit extracellular signalsacross the membrane. Caveolins are the main structural proteins residing in the caveolae. Caveolins and another category of newly identified caveolae regulatory proteins, named cavins, are not only responsible for caveolae formation, but also interact with signaling complexes in the caveolae and regulate transmission of signals across the membrane. In the lung, two of the three caveolin isoforms, i.e., cav-1 and-2, are expressed ubiquitously. Cavin protein family is composed of four proteins, named cavin-1(or PTRF for polymerase Ⅰ and transcript release factor), cavin-2(or SDPR for serum deprivation protein response), cavin-3(or SRBC for sdr-related gene product that binds to-c-kinase) and cavin-4(or MURC for muscle restricted coiled-coiled protein or cavin-4). All the caveolin and cavin proteins are essential regulators for caveolae dynamics. Recently, emerging evidence suggest that caveolae and its associated proteins play crucial roles in development and progression of pulmonary hypertension. The focus of this review is to outline and discuss the contrast in alteration of cav-1(cav-1),-2 and cavin-1(PTRF) expression and downstream signaling mechanisms between human and experimental models of pulmonary hypertension.展开更多
BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, mo...BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, monocrotaline(MCT) injection leads to progressive disruption of endothelial cells(EC), and endothelial caveolin-1(cav-1) loss, accompanied by the activation of pro-proliferative pathways leading to PH. Four weeks post-MCT, extensive endothelial cav-1 loss is associated with increased cav-1 expression in smooth muscle cells(SMC). Exposing the MCTtreated rats to hypoxia hastens the disease process; and at 4 wk, neointimal lesions and occlusion of the small arteries are observed.AIM To identify the alterations that occur during the progression of PH that lead to neointima formation.METHODS Male Sprague-Dawley rats(150-175 g) were divided in 4 groups(n = 6-8 per group): controls(C); MCT(M, a single sc injection 40 mg/kg); Hypoxia(H,hypobaric hypoxia); MCT + hypoxia(M+H, MCT-injected rats subjected to hypobaric hypoxia starting on day1). Four weeks later, right ventricular systolic pressure(RVSP), right ventricular hypertrophy(RVH), lung histology, and cav-1 localization using immunofluorescence technique were analyzed. In addition, the expression of cav-1, tyrosine 14 phosphorylated cav-1(p-cav-1), caveolin-2(cav-2), cavin-1, vascular endothelial cadherin(VE-Cad) and p-ERK1/2 in the lungs were examined, and the results were compared with the controls.RESULTSSignificant PH and right ventricular hypertrophy were present in M and H groups [RVSP, mmHg, M 54±5~*, H 45±2~*, vs C 20±1, P < 0.05; RVH, RV/LV ratio M 0.57±0.02~*, H 0.50±0.03~*, vs C 0.23±0.007, P < 0.05]; with a further increase in M+H group [RVSP 69±9 mmHg, RV/LV 0.59±0.01 P < 0.05 vs M and H]. All experimental groups revealed medial hypertrophy; but only M+H group exhibited small occluded arteries and neointimal lesions. Immunofluorescence studies revealed endothelial cav-1 loss and increased cav-1 expression in SMC in M group; however, the total cav-1 level in the lungs remained low. In the M+H group, significant endothelial cav-1 loss was associated with increasing expression of cav-1 in SMC; resulting in near normalization of cav-1 levels in the lungs [cav-1, expressed as % control, C 100±0, M 22±4~*, H 96±7, M+H 77±6, ~* = P< 0.05 vs C]. The expression of p-cav-1 was observed in M and M+H groups [M314±4%, M+H 255±22% P < 0.05 vs C]. Significant loss of cav-2 [% control, C100±0, M 15±1.4~*, H 97±7, M+H 15±2~*; M and M+H vs C, ~* = P < 0.05], cavin-1 [%control, C 100±0, M 20±3~*, H 117±7, M+H 20±4~*; M and M+H vs C, P < 0.05] and VE-Cad [% control, C 100±0, M 17±4~*, H 96±9, M+H 8±3~*; M and M+H vs C, P <0.05] was present in M and M+H groups, confirming extensive disruption of EC.Hypoxia alone did not alter the expression of cav-1 or cav-1 related proteins.Expression of p-ERK1/2 was increased in all 3 PH groups [%control, C 100±0, M284±23~*, H 254±25~*, M+H 270±17~*; ~* = P < 0.05 vs C].CONCLUSION Both cavin-1 loss and p-cav-1 expression are known to facilitate cell migration;thus, these alterations may in part play a role in neointima formation in PH.展开更多
聚合酶Ⅰ和转录本释放因子(polymerase-1 and transcript release factor,PTRF/Cavin-1),最初因参与基因转录终止过程被报道,随后发现其可与细胞膜上小凹蛋白结合,通过参与细胞质膜小凹形成促进外泌体分泌,调节全身脂质代谢等。先天性...聚合酶Ⅰ和转录本释放因子(polymerase-1 and transcript release factor,PTRF/Cavin-1),最初因参与基因转录终止过程被报道,随后发现其可与细胞膜上小凹蛋白结合,通过参与细胞质膜小凹形成促进外泌体分泌,调节全身脂质代谢等。先天性全身性脂肪营养不良患者常见PTRF/Cavin-1基因突变/缺失。在胶质瘤中,PTRF/Cavin-1不仅可作为提示患者预后的标记物,还可通过影响肿瘤细胞内吞和外分泌、肿瘤脂质代谢重编程、重塑肿瘤细胞外基质等多种途径促进肿瘤恶性行为发生。本文归纳整理了PTRF/Cavin-1在胶质瘤中的多功能性,有助于全面理解其促进肿瘤发展的分子机制,开发针对PTRF/Cavin-1的胶质瘤靶向药物。展开更多
文摘Caveolae are flask-shaped invaginations of cell membrane that play a significant structural and functional role. Caveolae harbor a variety of signaling molecules and serve to receive, concentrate and transmit extracellular signalsacross the membrane. Caveolins are the main structural proteins residing in the caveolae. Caveolins and another category of newly identified caveolae regulatory proteins, named cavins, are not only responsible for caveolae formation, but also interact with signaling complexes in the caveolae and regulate transmission of signals across the membrane. In the lung, two of the three caveolin isoforms, i.e., cav-1 and-2, are expressed ubiquitously. Cavin protein family is composed of four proteins, named cavin-1(or PTRF for polymerase Ⅰ and transcript release factor), cavin-2(or SDPR for serum deprivation protein response), cavin-3(or SRBC for sdr-related gene product that binds to-c-kinase) and cavin-4(or MURC for muscle restricted coiled-coiled protein or cavin-4). All the caveolin and cavin proteins are essential regulators for caveolae dynamics. Recently, emerging evidence suggest that caveolae and its associated proteins play crucial roles in development and progression of pulmonary hypertension. The focus of this review is to outline and discuss the contrast in alteration of cav-1(cav-1),-2 and cavin-1(PTRF) expression and downstream signaling mechanisms between human and experimental models of pulmonary hypertension.
基金Supported in part by Cardiovascular Medical Research and Education Fund
文摘BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, monocrotaline(MCT) injection leads to progressive disruption of endothelial cells(EC), and endothelial caveolin-1(cav-1) loss, accompanied by the activation of pro-proliferative pathways leading to PH. Four weeks post-MCT, extensive endothelial cav-1 loss is associated with increased cav-1 expression in smooth muscle cells(SMC). Exposing the MCTtreated rats to hypoxia hastens the disease process; and at 4 wk, neointimal lesions and occlusion of the small arteries are observed.AIM To identify the alterations that occur during the progression of PH that lead to neointima formation.METHODS Male Sprague-Dawley rats(150-175 g) were divided in 4 groups(n = 6-8 per group): controls(C); MCT(M, a single sc injection 40 mg/kg); Hypoxia(H,hypobaric hypoxia); MCT + hypoxia(M+H, MCT-injected rats subjected to hypobaric hypoxia starting on day1). Four weeks later, right ventricular systolic pressure(RVSP), right ventricular hypertrophy(RVH), lung histology, and cav-1 localization using immunofluorescence technique were analyzed. In addition, the expression of cav-1, tyrosine 14 phosphorylated cav-1(p-cav-1), caveolin-2(cav-2), cavin-1, vascular endothelial cadherin(VE-Cad) and p-ERK1/2 in the lungs were examined, and the results were compared with the controls.RESULTSSignificant PH and right ventricular hypertrophy were present in M and H groups [RVSP, mmHg, M 54±5~*, H 45±2~*, vs C 20±1, P < 0.05; RVH, RV/LV ratio M 0.57±0.02~*, H 0.50±0.03~*, vs C 0.23±0.007, P < 0.05]; with a further increase in M+H group [RVSP 69±9 mmHg, RV/LV 0.59±0.01 P < 0.05 vs M and H]. All experimental groups revealed medial hypertrophy; but only M+H group exhibited small occluded arteries and neointimal lesions. Immunofluorescence studies revealed endothelial cav-1 loss and increased cav-1 expression in SMC in M group; however, the total cav-1 level in the lungs remained low. In the M+H group, significant endothelial cav-1 loss was associated with increasing expression of cav-1 in SMC; resulting in near normalization of cav-1 levels in the lungs [cav-1, expressed as % control, C 100±0, M 22±4~*, H 96±7, M+H 77±6, ~* = P< 0.05 vs C]. The expression of p-cav-1 was observed in M and M+H groups [M314±4%, M+H 255±22% P < 0.05 vs C]. Significant loss of cav-2 [% control, C100±0, M 15±1.4~*, H 97±7, M+H 15±2~*; M and M+H vs C, ~* = P < 0.05], cavin-1 [%control, C 100±0, M 20±3~*, H 117±7, M+H 20±4~*; M and M+H vs C, P < 0.05] and VE-Cad [% control, C 100±0, M 17±4~*, H 96±9, M+H 8±3~*; M and M+H vs C, P <0.05] was present in M and M+H groups, confirming extensive disruption of EC.Hypoxia alone did not alter the expression of cav-1 or cav-1 related proteins.Expression of p-ERK1/2 was increased in all 3 PH groups [%control, C 100±0, M284±23~*, H 254±25~*, M+H 270±17~*; ~* = P < 0.05 vs C].CONCLUSION Both cavin-1 loss and p-cav-1 expression are known to facilitate cell migration;thus, these alterations may in part play a role in neointima formation in PH.
文摘聚合酶Ⅰ和转录本释放因子(polymerase-1 and transcript release factor,PTRF/Cavin-1),最初因参与基因转录终止过程被报道,随后发现其可与细胞膜上小凹蛋白结合,通过参与细胞质膜小凹形成促进外泌体分泌,调节全身脂质代谢等。先天性全身性脂肪营养不良患者常见PTRF/Cavin-1基因突变/缺失。在胶质瘤中,PTRF/Cavin-1不仅可作为提示患者预后的标记物,还可通过影响肿瘤细胞内吞和外分泌、肿瘤脂质代谢重编程、重塑肿瘤细胞外基质等多种途径促进肿瘤恶性行为发生。本文归纳整理了PTRF/Cavin-1在胶质瘤中的多功能性,有助于全面理解其促进肿瘤发展的分子机制,开发针对PTRF/Cavin-1的胶质瘤靶向药物。
