Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung

Ravi, Y.; Selvendiran, Karuppaiyah; Naidu, Shan K.; Meduru, Sarath; Citro, Lucas; Bognár, Balázs; Khan, Mahmood; Kálai, Tamás; Hideg, Kálmán; Kuppusamy, Periannan; Sai-Sudhakar, Chittoor

doi:10.1161/hypertensionaha.111.00514

Cited by 25 publications

(19 citation statements)

References 39 publications

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“…Our results are in agreement with a previous study by Yazhini et al (Ravi, Selvendiran, 2013b), which showed a significant reduction in the expression of PTEN in the lungs of mice with PAH induced by hypoxia and PASMCs by peroxynitrite treatment. Immunohistochemical staining and protein data from our experiments further showed that AKT, a downstream target of the PTEN antagonist PI3K, was markedly activated in the lungs，PAs and PASMCs.…”

Section: Discussionsupporting

confidence: 94%

“…Immunohistochemical staining and protein data from our experiments further showed that AKT, a downstream target of the PTEN antagonist PI3K, was markedly activated in the lungs，PAs and PASMCs. This relation between PTEN and AKT is consistent with the previous studies on the monocrotaline or hypoxia models of PAH (Ravi, Selvendiran, 2013b).…”

Section: Discussionsupporting

confidence: 92%

“…Loss or down-regulation of PTEN plays an important role in development and progression of human cancer, including pancreatic cancer, lung cancer and glioblastoma (Fenton et al , 2012, Ying et al , 2011. Previous studies have suggested that PTEN participates in the negative regulation of SMC proliferation associated with vascular remodeling (Nemenoff et al , 2008, Ravi, Selvendiran, 2013b. PTEN was significantly reduced in the lung tissues of rats administered with monocrotaline or exposed to chronic hypoxia (Ravi et al , 2013a).…”

Section: Discussionmentioning

confidence: 99%

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Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Liu

Cao

Sun

et al. 2016

The International Journal of Biochemistry & Cell Biology

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Liu

Cao

Sun

et al. 2016

The International Journal of Biochemistry & Cell Biology

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“…We previously demonstrated that cardiovascular depletion of PTEN resulted in pulmonary vascular remodeling consistent with pulmonary hypertension . In addition, Ravi, et al reported dysregulation of PTEN in monocrotaline‐ and hypoxia‐induced PH as well as in PH secondary to left heart failure supporting an important role for PTEN in SMCs on PH progression. However, the direct role of SMC PTEN inactivation on the progression of PH is unclear.…”

Section: Introductionmentioning

confidence: 99%

Selective Inactivation of PTEN in Smooth Muscle Cells Synergizes With Hypoxia to Induce Severe Pulmonary Hypertension

Horita

Furgeson

Ostriker

et al. 2013

JAHA

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BackgroundPulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia‐induced PH using a mouse model with inducible deletion of PTEN in SMCs.Methods and ResultsStaining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild‐type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs.ConclusionsChronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease.

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“…Several experimental models of PH due to cardiac dysfunction have brought important insights into this area. In a descending coronary artery ligation post MI model, abnormalities in the lung microcirculation consisted of increased oxidative stress and diffuse inflammation 14 .…”

mentioning

confidence: 99%

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

Guazzi¹,

Phillips²,

Arena³

et al. 2015

Progress in Cardiovascular Diseases

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Cardiac dysfunction of both systolic and diastolic origin leads to increased left atrial pressure, lung capillary injury and increased resistance to gas transfer. Acutely, pressure-induced trauma disrupts the endothelial and alveolar anatomical configuration and definitively causes an impairment of cellular pathways involved in fluid-flux regulation and gas exchange efficiency, a process well identified as stress failure of the alveolarcapillary membrane. In chronic heart failure (HF), additional stimuli other than pressure may trigger the true remodeling process of capillaries and small arteries characterized by endothelial dysfunction, proliferation of myofibroblasts, fibrosis and extracellular matrix deposition. In parallel there is a loss of alveolar gas diffusion properties due to the increased path from air to blood (thickening of extracellular matrix) and loss of fine molecular mechanism involved in fluid reabsorption and clearance. Deleterious changes in gas transfer not only reflect the underlying lung tissue damage but also portend independent prognostic information and may play a role in the pathogenesis of exercise limitations and ventilatory abnormalities observed in these patients. Few currently approved treatments for chronic HF have the potential to positively affect structural remodeling of the lung capillary network; angiotensin-converting enzyme inhibitors are one of the few currently established options. Recently, more attention has been paid to novel therapies specifically targeting the nitric oxide pathway as a suitable target to improve endothelial function and permeability as well as alveolar gas exchange properties.

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Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung

Cited by 25 publications

References 39 publications

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

Selective Inactivation of PTEN in Smooth Muscle Cells Synergizes With Hypoxia to Induce Severe Pulmonary Hypertension

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

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