Dysregulation of PTEN in Cardiopulmonary Vascular Remodeling Induced by Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a disorder of lung vasculature characterized by arterial narrowing. Phosphatase-and-tensin homolog on chromosome 10 (PTEN), associated in the progression of multiple cancers, is implicated in arterial remodeling. However, the involvement of PTEN in PH remains unclear. The objective of the present study was to determine the role of PTEN in pulmonary vascular remodeling using established models of PH. The study used rat models of PH, induced by monocrotaline (MCT) administration (60 mg/kg) or continuous hypoxic exposure (10% oxygen) for 3 weeks. Pulmonary artery smooth muscle cells (SMCs) were used for in vitro confirmation. Development of PH was verified by hemodynamic, morphological and histopathology analyses. PTEN and key downstream proteins in pulmonary and cardiac tissues were analyzed by western blotting and RT-PCR. PTEN was significantly decreased (MCT, 53%; Hypoxia, 40%), pAkt was significantly increased (MCT, 42%; Hypoxia, 55%) in tissues of rats with PH. Similar results were observed in SMCs exposed to hypoxia (1% oxygen) for 48 h. Ubiquitination assay showed that PTEN degradation occurs via proteasomal degradation pathway. Western blotting demonstrated a significant downregulation of cell-cycle regulatory proteins p53 and p27, and upregulation of cyclin-D1 in the lungs of both models. The results showed that PTEN-mediated modulation of PI3K pathway was independent of the focal adhesion kinase and fatty acid synthase. The study, for the first time, established that PTEN plays a key role in the progression of pulmonary hypertension. The findings may have potential for the treatment of pulmonary hypertension using PTEN as a target.

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

“…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).…”

Targeting cell motility in pulmonary arterial hypertension

“…It has been demonstrated that p53 regulation, which is protective against PAH [8] and downregulated in MCT-PAH [12], is dependent on FAK nuclear translocation. Indeed, FAK inactivates p53 in a kinase-independent manner via its FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin), acting as a scaffold protein to enhance Mdm2-dependent p53 ubiquitination and degradation [51][52][53][54].…”

“…In some patients, there is a genetic predisposition due to heterozygous mutations in the bone morphogenetic type II receptor (BMPR-II) leading to an impaired function of SMAD (mothers against decapentaplegic homolog) pathways [4,5] and increased p38/ MAPK (mitogen-activated protein kinase) activation [6,7]. p53, p21, p27 and survivin are all tumour suppressor/oncogenic proteins that have also been implicated in PAH [1,[8][9][10][11][12]. We recently showed the critical role of the oncogenic axis c-Src (v-src sarcoma Schmidt-Ruppin A-2 viral oncogene homolog)/ STAT3 (signal transducer and activator of transcription 3)/Pim-1 (provirus integration site for Moloney murine leukaemia virus 1), accounting for increased expression and activation of the transcription factor NFAT (nuclear factor of activated T-cells) [13][14][15] and explaining several recognised features of PAHPASMCs including: 1) downregulation of the voltage-gated K + channel 1.5 (Kv1.5), which depolarises PASMCs, increasing intracellular Ca 2+ ([Ca 2+ ] i ), and promoting proliferation); and 2) mitochondrial membrane potential (DYm) hyperpolarisation and inhibition of mitochondria-derived reactive oxygen species (mROS) generation, both of which suppress apoptosis [16].…”

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

“…6,7 PTEN is a dual-function phosphatase capable of dephosphorylating both lipids and proteins and it negatively regulates PI3K pathway by dephosphorylating phosphatidyl-inositol-triphosphate and pAkt, and hence regulates apoptosis and cell-proliferation pathways. Downregulation of PTEN is linked to smooth muscle cell (SMC) proliferation and vascular remodeling in animal models of arterial restenosis, 6–8 PH, 6 and lung fibrosis.…”