scholarly journals P15‐2: Activation of cleaved caspase‐3 in young rats of emphysema with pulmonary hypertension induced by SU5416

Respirology ◽  
2021 ◽  
Vol 26 (S3) ◽  
pp. 441-441
Keyword(s):  
Pulmonary Hypertension ◽  
Caspase 3 ◽  
Young Rats

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.

Contribution of peptidyl prolyl isomerase (Pin1) to development of pulmonary hypertension via pulmonary vascular endothelial cell dysfunction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Sakai ◽  
H Maruyama ◽  
M Ieda
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Western Blot ◽  
Caspase 3 ◽  
Pulmonary Arterial Pressure ◽  
Funding Source ◽  
Enos Expression ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is thought to be a major contributor to overall pathogenesis of vasculopathy seen in pulmonary hypertension (PH), which is manifested by the impaired release of nitric oxide (NO) generated through endothelial nitric oxide synthase (eNOS) in endothelial cells. Activation of human eNOS is regulated by phosphorylation at multiple sites including Thr33 and Ser114, which residues are followed by Pro. The peptidyl isomerase Pin1 specifically isomerizes the phospho-protein having Ser/Thr-Pro bond and regulates their activity. Pin1 is involved in proliferation, cell cycle, and apoptosis in cancer, by isomerizing some functional molecules such as JNK, JUN, cyclin D, BAX, etc. However, it is controversial whether direct interaction of Pin1 with eNOS and how eNOS activity is altered by Pin1, especially in PH. Purpose We aimed to clarify whether Pin1 contributes to the PH development using Pin1 knockout mice and Pin1 affects the expression of phosphorylated eNOS (p-eNOS) molecule and pulmonary arterial endothelial cell (PAEC) apoptosis. Methods and results Wild (WT) and Pin1-deficient mice (KO) were exposed to hypoxia (10% O2) or normoxia for 3 weeks to generate hypoxia-induced PH. Hypoxia-inducible factor (HIF1α) expression in lungs was significantly enhanced in WT-hypoxia (WH, n=6) and KO-hypoxia (KH, n=6), suggesting that hypoxic response was certainly occurred in these mice. Pulmonary arterial pressure did not elevate in KH compared with KO-normoxia (KN, n=6) and WT-normoxia (WN, n=6), it was significantly increased only in WH (P<0.01), indicating that KO did not develop PH by hypoxia. The gain of RV weight was parallel to the increase of pulmonary arterial pressure. Western blot showed that p-eNOS expression in lungs was significantly decreased in WH compared to WN, however, the expression was not different between KH and KN. It suggests that Pin1 plays a regulatory role in p-eNOS expression in hypoxic response. In cultured PAECs, the expression of p-eNOS and eNOS was markedly increased by siRNA-mediated Pin1 knockdown. Immunoprecipitation study showed the possibility of Pin1 binding to p-eNOS molecule. Apoptosis evaluated by caspase-3/7 activity by fluorescent assay and cleaved caspase-3 expression by Western blot was significantly increased by Pin1 overexpression in PAECs; however, it was significantly decreased by Pin1 knockdown. Moreover, the exaggeration of apoptosis induced by doxorubicin was markedly increased by Pin1 overexpression compared with control in PAECs; however, it was clearly suppressed by Pin1 knockdown. Conclusion This study suggests that endogenous Pin1 contributes to the development of PH partly via the dysfunction of PAECs, that is, by the interference with p-eNOS expression and by the increase of apoptosis inducibility to external stimuli. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

scholarly journals Endothelial Apoptosis in Pulmonary Hypertension Is Controlled by a microRNA/Programmed Cell Death 4/Caspase-3 Axis

Hypertension ◽  
2014 ◽  
Vol 64 (1) ◽  
pp. 185-194 ◽  
Author(s):  
Kevin White ◽  
Yvonne Dempsie ◽  
Paola Caruso ◽  
Emma Wallace ◽  
Robert A. McDonald ◽  
...  
Keyword(s):  
Cell Death ◽  
Pulmonary Hypertension ◽  
Programmed Cell Death ◽  
Caspase 3 ◽  
Endothelial Apoptosis ◽  
Programmed Cell Death 4

Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension

2006 ◽  
Vol 291 (4) ◽  
pp. L668-L676 ◽  
Author(s):  
Laimute Taraseviciene-Stewart ◽  
Robertas Scerbavicius ◽  
Kang-Hyeon Choe ◽  
Carlyne Cool ◽  
Kathy Wood ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Right Ventricular ◽  
Cell Apoptosis ◽  
Ventricular Hypertrophy ◽  
Caspase 3 ◽  
Right Ventricular Hypertrophy ◽  
Severe Pulmonary Hypertension ◽  
Endothelial Cell Apoptosis ◽  
Microvascular Endothelial

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-γ agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.

scholarly journals DDAH1 SNP rs480414 that protects against the development of pulmonary hypertension in bronchopulmonary dysplasia results in lower nitric oxide production in neonatal cord blood-derived lymphoblastoid cell lines

2021 ◽  
pp. 1-9
Author(s):  
Avante D. Milton ◽  
Hanadi Almazroue ◽  
Yi Jin ◽  
Gloria Zender ◽  
Jennifer K. Trittmann
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Cord Blood ◽  
Mrna Expression ◽  
Cell Lines ◽  
Bronchopulmonary Dysplasia ◽  
Caspase 3 ◽  
Inos Mrna ◽  
No Production ◽  
Lymphoblastoid Cell Lines

BACKGROUND: Bronchopulmonary dysplasia (BPD) is chronic lung disease of prematurity and pulmonary hypertension (PH) is a major contributor to morbidity and mortality in BPD patients. Nitric oxide (NO) is a vasodilator and apoptotic mediator made by NO synthase (NOS). NOS is inhibited by asymmetric dimethylarginine (ADMA), and dimethylarginine dimethylaminohydrolase (DDAH) hydrolyzes ADMA. Previously, in a BPD patient cohort, we identified single nucleotide polymorphism (SNP) DDAH1 rs480414 (G >  A) that was protective against developing PH. This study aims to determine functional consequences of the DDAH1 SNP in lymphoblastoid cell lines (LCLs) derived from neonatal cord blood. We tested the hypothesis that DDAH1 SNP (AA) results in DDAH1 gain of function, leading to greater NO-mediated apoptosis compared to DDAH1 wild-type (GG) in LCLs. METHODS: LCLs were analyzed by Western blot (DDAH1, cleaved and total caspase-3 and -8, and β-actin), and RT-PCR (DDAH1, iNOS). Cell media assayed for nitrites with chemiluminescence NO analyzer, and conversion of ADMA to L-citrulline was measured by spectrophotometry. RESULTS: LCLs with DDAH1 SNP had similar levels of DDAH1 protein and mRNA expression, as well as DDAH activity, compared to DDAH1 WT LCLs. There were also no changes in cleaved caspase-3 and -8 protein levels. LCLs with DDAH1 SNP had similar iNOS mRNA expression. Nitrite levels in media were lower for DDAH1 SNP LCLs compared to DDAH1 WT LCLs (p <  0.05). CONCLUSION: Contrary to our hypothesis, we found that NO production was lower in DDAH1 SNP LCLs, indicative of a loss of function phenotype.

Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension

2006 ◽  
Vol 290 (3) ◽  
pp. L450-L458 ◽  
Author(s):  
Hideki Takahashi ◽  
Naoto Goto ◽  
Yuko Kojima ◽  
Yasunari Tsuda ◽  
Yoshiteru Morio ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Bone Morphogenetic Protein ◽  
P38 Mapk ◽  
Caspase 3 ◽  
Bmp Signaling ◽  
Pulmonary Vasculature ◽  
Type Ii ◽  
Morphogenetic Protein

Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR-II) and dysfunction of BMPR-II have been implicated in patients with primary pulmonary hypertension (PH). To clarify the possible involvement of BMP and BMPR-II in the development of hypoxic PH, the expression of BMP-2, BMPR-II, and their downstream signals were investigated in rat lung under normal and hypoxic conditions by RT-PCR, immunoblot, and immunohistochemical methods. In rats under normal conditions, BMP-2 is localized in the endothelium of the pulmonary artery, whereas BMPR-II is abundantly expressed in the endothelium, smooth muscle cells, and adventitial fibroblasts. After 0.5 and 3 days of exposure to hypoxia, upregulation of BMP-2 was observed in the intrapulmonary arteries. The change was accompanied by activation of its downstream signaling, p38 MAPK, and Erk1/2 MAPK, and the apoptotic process, measured by caspase-3 activity and TdT-mediated dUTP nick end labeling-positive cells. In contrast, a significant decrease in the expression of BMPR-II and inactivation of p38 MAPK and caspase-3 were observed in the pulmonary vasculature after 7–21 days of hypoxia exposure. Because BMP-2 is known to inhibit proliferation of vascular smooth muscle cells and promote cellular apoptosis, disruption of BMP signaling pathway through downregulation of BMPR-II in chronic hypoxia may result in pulmonary vascular remodeling due to the failure of critical antiproliferative/differentiation programs in the pulmonary vasculature. These results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.

Porto-pulmonary hypertension in decompensated cirrhosis and refractory ascites

2001 ◽  
Vol 120 (5) ◽  
pp. A377-A377
Author(s):  
F BENJAMINOV ◽  
K SNIDERMAN ◽  
S SIU ◽  
P LIU ◽  
M PRENTICE ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Refractory Ascites ◽  
Decompensated Cirrhosis
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