scholarly journals Alterations in Caveolin-1 Expression and Receptor-Operated Ca2+ Entry in the Aortas of Rats with Pulmonary Hypertension

2016 ◽  
Vol 39 (2) ◽  
pp. 438-452 ◽  
Author(s):  
Yun-Ping Mu ◽  
Da-Cen Lin ◽  
Fu-Rong Yan ◽  
Hai-Xia Jiao ◽  
Long-Xin Gui ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cardiovascular Diseases ◽  
Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Muscle Cells ◽  
Pathological Process ◽  
Functional Changes ◽  
Caveolin 1 ◽  
Ca2 Channels

Background/Aims: Alterations in intracellular Ca2+ concentration ([Ca2+]i) underlie the pathogenesis of various cardiovascular diseases. Caveolin-1 (Cav-1) is the primary functional protein associated with caveolae, which are invaginations in the plasma membrane, and is a regulator of [Ca2+]i signaling. Caveolae and Cav-1 increase the activity of store-operated Ca2+ channels (SOCC) in rat pulmonary arterial smooth muscle cells (PASMCs), and these enhancing effects were more pronounced in rats with pulmonary hypertension (PH). Classical transient receptor potential (TRPC) proteins are highly expressed in vascular smooth muscle cells, and these proteins form functional receptor-operated Ca2+ channels (ROCC) and SOCC in PASMCs. Previous studies suggested that functional and structural changes in aortas might occur during the pathological process of PH. Our data demonstrated that Cav-1 and TRPC were also abundant in the aorta smooth muscle cells (AoSMCs) of PH rats. However, previous PH research primarily focused on Ca2+ channels in pulmonary arteries, but not functional changes in Ca2+ channels in aortas. The contribution of Cav-1 of AoSMCs to alterations of Ca2+ signaling in aortic functions during the pathological process of PH has not been fully characterized. Therefore, this study investigated alterations in Cav-1 expression and the relationship of these changes to Ca2+ channels in AoSMCs of PH rats. Methods: The present study examined physiological caveolae and Cav-1 expression and characterized the function of altered Cav-1 expression in rat aortas with PH. Results: The appearance of caveolae with Cav-1 expression increased significantly in the aortas of rats with PH, but TRPC1 and TRPC6 expression was not altered. In vitro experiments demonstrated that caveolae contributed to phenylephrine, endothelin-1, and 1-oleoyl-2-acetyl-sn-glycerol (OAG)-induced aortic vasoreactivity, but KCl and cyclopiazonic acid had no effect, which suggests the vital ability of Cav-1 to regulate ROCC activity. The introduction of Cav-1 scaffolding domain peptide enhanced OAG-induced ROCC function in primary AoSMCs. Conclusion: Cav-1 is specifically associated with ROCC in aortas and plays a vital role in altering vasoreactivity, which affects cardiovascular diseases pathology. Caveolae and Cav-1 up-regulation may affect the function of ROCC in rat models of PH.

scholarly journals Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension

2019 ◽  
Vol 316 (1) ◽  
pp. L216-L228 ◽  
Author(s):  
Ziyi Wang ◽  
Kai Yang ◽  
Qiuyu Zheng ◽  
Chenting Zhang ◽  
Haiyang Tang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Muscle Cells ◽  
Transient Receptor Potential Channels ◽  
Nuclear Accumulation ◽  
Pulmonary Vascular Disease ◽  
Pulmonary Arterial

The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]cyt). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.

scholarly journals The Role and Regulation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Shixin He ◽  
Tengteng Zhu ◽  
Zhenfei Fang
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cardiovascular Diseases ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Molecular Basis ◽  
Muscle Cells ◽  
Potential Treatment ◽  
Pulmonary Artery Smooth Muscle

Pulmonary hypertension (PH) is one of the most devastating cardiovascular diseases worldwide and it draws much attention from numerous scientists. As an indispensable part of pulmonary artery, smooth muscle cells are worthy of being carefully investigated. To elucidate the pathogenesis of PH, several theories focusing on pulmonary artery smooth muscle cells (PASMC), such as hyperproliferation, resistance to apoptosis, and cancer theory, have been proposed and widely studied. Here, we tried to summarize the studies, concentrating on the role of PASMC in the development of PH, feasible molecular basis to intervene, and potential treatment to PH.

scholarly journals Cell-Specific Dual Role of Caveolin-1 in Pulmonary Hypertension

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Rajamma Mathew
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Dual Role ◽  
Scaffolding Protein ◽  
Suppressor Factor ◽  
Caveolin 1 ◽  
Enhanced Expression

A wide variety of cardiopulmonary and systemic diseases are known to lead to pulmonary hypertension (PH). A number of signaling pathways have been implicated in PH; however, the precise mechanism/s leading to PH is not yet clearly understood. Caveolin-1, a membrane scaffolding protein found in a number of cells including endothelial and smooth muscle cells, has been implicated in PH. Loss of endothelial caveolin-1 is reported in clinical and experimental forms of PH. Caveolin-1, also known as a tumor-suppressor factor, interacts with a number of transducing molecules that reside in or are recruited to caveolae, and it inhibits cell proliferative pathways. Not surprisingly, the rescue of endothelial caveolin-1 has been found not only to inhibit the activation of proliferative pathways but also to attenuate PH. Recently, it has emerged that during the progression of PH, enhanced expression of caveolin-1 occurs in smooth muscle cells, where it facilitates cell proliferation, thus contributing to worsening of the disease. This paper summarizes the cell-specific dual role of caveolin-1 in PH.

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

2014 ◽  
Vol 306 (1) ◽  
pp. H15-H25 ◽  
Author(s):  
Rajamma Mathew
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cell Membrane ◽  
Smooth Muscle Cells ◽  
Right Ventricular ◽  
Membrane Integrity ◽  
Muscle Cells ◽  
Major Protein ◽  
Cell Membrane Integrity ◽  
Caveolin 1

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.

Elevated levels of activin A in clinical and experimental pulmonary hypertension

2009 ◽  
Vol 106 (4) ◽  
pp. 1356-1364 ◽  
Author(s):  
Arne Yndestad ◽  
Karl-Otto Larsen ◽  
Erik Øie ◽  
Thor Ueland ◽  
Camilla Smith ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor ◽  
Experimental Studies ◽  
Plasminogen Activator Inhibitor ◽  
Muscle Cells ◽  
Activin A ◽  
Plasminogen Activator Inhibitor 1 ◽  
And Control

Activin A, a member of the transforming growth factor (TGF)-β superfamily, is involved in regulation of tissue remodeling and inflammation. Herein, we wanted to explore a role for activin A in pulmonary hypertension (PH). Circulating levels of activin A and its binding protein follistatin were measured in patients with PH ( n = 47) and control subjects ( n = 14). To investigate synthesis and localization of pulmonary activin A, we utilized an experimental model of hypoxia-induced PH. In mouse lungs, we also explored signaling pathways that can be activated by activin A, such as phosphorylation of Smads, which are mediators of TGF-β signaling. Possible pathophysiological mechanisms initiated by activin A were explored by exposing pulmonary arterial smooth muscle cells in culture to this cytokine. Elevated levels of activin A and follistatin were found in patients with PH, and activin A levels were significantly related to mortality. Immunohistochemistry of lung autopsies from PH patients and lungs with experimental PH localized activin A primarily to alveolar macrophages and bronchial epithelial cells. Mice with PH exhibited increased pulmonary levels of mRNA for activin A and follistatin in the lungs, and also elevated pulmonary levels of phosphorylated Smad2. Finally, we found that activin A increased proliferation and induced gene expression of endothelin-1 and plasminogen activator inhibitor-1 in pulmonary artery smooth muscle cells, mediators that could contribute to vascular remodeling. Our findings in both clinical and experimental studies suggest a role for activin A in the development of various types of PH.

scholarly journals The Contraction of Smooth Muscle Cells of Intrapulmonary Arterioles Is Determined by the Frequency of Ca2+ Oscillations Induced by 5-HT and KCl

2005 ◽  
Vol 125 (6) ◽  
pp. 555-567 ◽  
Author(s):  
Jose F. Perez ◽  
Michael J. Sanderson
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Confocal Microscopy ◽  
Smooth Muscle Cells ◽  
Phase Contrast ◽  
Muscle Cells ◽  
Low Frequencies ◽  
Scanning Confocal Microscopy ◽  
Agonist Concentration ◽  
Mouse Lungs

Increased resistance of the small blood vessels within the lungs is associated with pulmonary hypertension and results from a decrease in size induced by the contraction of their smooth muscle cells (SMCs). To study the mechanisms that regulate the contraction of intrapulmonary arteriole SMCs, the contractile and Ca2+ responses of the arteriole SMCs to 5-hydroxytrypamine (5-HT) and KCl were observed with phase-contrast and scanning confocal microscopy in thin lung slices cut from mouse lungs stiffened with agarose and gelatin. 5-HT induced a concentration-dependent contraction of the arterioles. Increasing concentrations of extracellular KCl induced transient contractions in the SMCs and a reduction in the arteriole luminal size. 5-HT induced oscillations in [Ca2+]i within the SMCs, and the frequency of these Ca2+ oscillations was dependent on the agonist concentration and correlated with the extent of sustained arteriole contraction. By contrast, KCl induced Ca2+ oscillations that occurred with low frequencies and were preceded by small, localized transient Ca2+ events. The 5-HT–induced Ca2+ oscillations and contractions occurred in the absence of extracellular Ca2+ and were resistant to Ni2+ and nifedipine but were abolished by caffeine. KCl-induced Ca2+ oscillations and contractions were abolished by the absence of extracellular Ca2+ and the presence of Ni2+, nifedipine, and caffeine. Arteriole contraction was induced or abolished by a 5-HT2–specific agonist or antagonist, respectively. These results indicate that 5-HT, acting via 5-HT2 receptors, induces arteriole contraction by initiating Ca2+ oscillations and that KCl induces contraction via Ca2+ transients resulting from the overfilling of internal Ca2+ stores. We hypothesize that the magnitude of the sustained intrapulmonary SMC contraction is determined by the frequency of Ca2+ oscillations and also by the relaxation rate of the SMC.

The Action of Shenmai Injection on the Inflammation and Proliferation of Smooth Muscle Cells of the Airway in Asthmatic Rats

2021 ◽  
Vol 11 (3) ◽  
pp. 386-391
Author(s):  
He Zhu ◽  
Yali Guo ◽  
Xiaoli Wang ◽  
Min Zhu ◽  
Jiahui Lei ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Muscle Cells ◽  
Interleukin 4 ◽  
Nuclear Antigen ◽  
Control Group ◽  
Airway Smooth Muscle Cells ◽  
Shenmai Injection

To observe the effect of transient receptor potential ankyrin 1 (TRPA1) channel on the proliferation and inflammation of airway smooth muscle cells (SMC) in asthmatic rats, the rats were randomly allocated into three treatment groups: control, asthma, and Shenmai injection (SMI), with 15 rats in each group. Asthmatic rat models were induced by ovalbumin (OVA) inhalation. Rats in the control and asthma groups were intraperitoneally injected 2 mL NS daily, whereas rats in the SMI treatment group were intraperitoneally injected with 2 mL SMI daily. RT-qPCR and western blotting were used to test for TRPA1 and proliferating cell nuclear antigen (PCNA) mRNA and protein expression. ELISA was used to test the expression of interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) in the serum. Compared with the control group, there were significantly higher levels of TRPA1 and PCNA mRNA and protein, as well as of IL-4, IL-5, and IL-13 in asthmatic rats (P< 0.05). After SMI treatment, there was significantly lower expression of TRPA1, PCNA, IL-4, IL-5, and IL-13 compared to the levels in asthmatic rats (P < 0.05). TRPA1, IL-4, IL-5, and IL-13 were highly expressed in the tracheal SMC of asthmatic rats. Inhibiting TRPA1, IL-4, IL-5, and IL-13 using SMI may be one of the mechanisms that can intervene chronic airway inflammation and asthma proliferation.

Enhance Smooth Muscle Cells Apoptosis Associated With Pulmonary Arterial Remodeling in Dogs Affected With Pulmonary Hypertension Secondary to Degenerative Mitral Valve Disease

2021 ◽  
Author(s):  
Siriwan Sakarin ◽  
Anudep Rungsipipat ◽  
Sirilak Disatian Surachetpong
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Mitral Valve ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Mitral Valve Disease ◽  
Caspase 3 ◽  
Muscle Cells ◽  
Pulmonary Arterial ◽  
Medial Thickening

Abstract Background: Degenerative mitral valve disease (DMVD) is the most common cause of pulmonary hypertension (PH) in dogs. Medial thickening of the pulmonary artery is a major histopathological change in PH. A decrease in apoptosis of pulmonary arterial smooth muscle cells (SMCs) may be the cause of medial thickening. This study aimed to demonstrate the expression of apoptosis molecules in the pulmonary artery of dogs affected with PH secondary to DMVD (DMVD+PH) compared to DMVD without PH (DMVD) and healthy dogs (control). Lung samples were collected from three groups including control (n=5), DMVD (n=7) and DMVD+PH (n=7) groups. Masson trichrome and apoptotic proteins including Bax, Bcl2 and caspase-3 and -8, were stained. Results: The medial thickness in the DMVD and DMVD+PH groups was greater than in the control group and it was greatest in the DMVD+PH group. Bax, Bcl2 and caspase-3 and -8 were expressed mainly in the medial layer of the pulmonary artery. The percentages of Bax and caspase-3 and -8 positive cells were higher in the DMVD group compared to the DMVD+PH group, whereas the percentage of Bcl2-positive cells was increased in the DMVD and DMVD+PH groups. These findings suggested that apoptosis of pulmonary arterial SMCs occurred mainly in the DMVD group and decreased dramatically in the DMVD+PH group. Conclusions: An increase in the medial thickness in dogs affected with PH secondary to DMVD may occur due to a decrease in apoptosis of pulmonary arterial SMCs.

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