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Pulmonary hypertension and metabolic syndrome: Possible connection, PPAR? and Caveolin-1.

ABSTRACT: A number of disparate diseases can lead to pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro- and anti-inflammatory adipokines that modulate vascular function and angiogenesis, suggesting a close functional relationship between the adipose tissue and the vasculature. Both caveolin-1, a cell membrane scaffolding protein and peroxisome proliferator-activated receptor (PPAR) ?, a ligand-activated transcription factor are abundantly expressed in the endothelial cells and adipocytes. Both caveolin-1 and PPAR? modulate proliferative and anti-apoptotic pathways, cell migration, inflammation, vascular homeostasis, and participate in lipid transport, triacylglyceride synthesis and glucose metabolism. Caveolin-1 and PPAR? regulate the production of adipokines and in turn are modulated by them. This review article summarizes the roles and inter-relationships of caveolin-1, PPAR? and adipokines in PH and metabolic syndrome.

SUBMITTER: Mathew R

PROVIDER: S-EPMC4163699 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1.

Mathew Rajamma R

World journal of cardiology 20140801 8

A number of disparate diseases can lead to pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate. Recent studies suggest that the associated metabolic dysregulation may be an important factor adversely impacting the prognosis of PH. Furthermore, metabolic syndrome is associated with vascular diseases including PH. Inflammation plays a significant role both in PH and metabolic syndrome. Adipose tissue modulates lipid and glucose metabolism, and also produces pro ...[more]

PMID: 25228949

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Project description:Background: In 2012, mutations in Cav1 were found to be the driving mutation in several cases of heritable pulmonary arterial hypertension (PAH). These mutations replaced the last 21 amino acids of Cav1 with a novel 22-amino-acid sequence. Because previously only Cav1 knockouts had been studied in the context of PAH, examining the in vivo effects of this novel mutation holds promise for new understanding of the role of Cav1 in disease etiology. Methods: The new 22 amino acids created by the human mutation were knocked into the native mouse Cav1 locus. The mice underwent hemodynamic, energy balance, and inflammatory measurements, both at baseline and after being stressed with either a metabolic or an inflammatory challenge [low-dose lipopolysaccharide (LPS)]. To metabolically challenge the mice, they were injected with streptozotocin (STZ) and fed a high-fat diet for 12 weeks. Results: Very little mutant protein was found in vivo (roughly 2% of wild-type by mass spectrometry), probably because of degradation after failure to traffic from the endoplasmic reticulum. The homozygous mutants developed a mild, low-penetrance PAH similar to that described previously in knockouts, and neither baseline nor metabolic nor inflammatory stress resulted in pressures above normal in heterozygous animals. The homozygous mutants had increased lean mass and worsened oral glucose tolerance, as previously described in knockouts. Novel findings include the preservation of Cav2 and accessory proteins in the liver and the kidney, while they are lost with homozygous Cav1 mutation in the lungs. We also found that the homozygous mutants had a significantly lower tolerance to voluntary spontaneous exercise than the wild-type mice, with the heterozygous mice at an intermediate level. The mutants also had higher circulating monocytes, with both heterozygous and homozygous animals having higher pulmonary MCP1 and MCP5 proteins. The heterozygous animals also lost weight at an LPS challenge level at which the wild-type mice continued to gain weight. Conclusions: The Cav1 mutation identified in human patients in 2012 is molecularly similar to a knockout of Cav1. It results in not only metabolic deficiencies and mild pulmonary hypertension, as expected, but also an inflammatory phenotype and reduced spontaneous exercise.

Project description:Hermansky-Pudlak Syndrome type-1 (HPS-1) is an autosomal recessive disorder caused by mutations in HPS1 which result in reduced expression of the HPS-1 protein, defective lysosome-related organelle (LRO) transport and absence of platelet delta granules. Patients with HPS-1 exhibit oculocutaneous albinism, colitis, bleeding and pulmonary fibrosis postulated to result from a dysregulated immune response. The effect of the HPS1 mutation on human mast cells (HuMCs) is unknown. Since HuMC granules classify as LROs along with platelet granules and melanosomes, we set out to determine if HPS-1 cutaneous and CD34+ culture-derived HuMCs have distinct granular and cellular characteristics. Cutaneous and cultured CD34+-derived HuMCs from HPS-1 patients were compared with normal cutaneous and control HuMCs, respectively, for any morphological and functional differences. One cytokine-independent HPS-1 culture was expanded, cloned, designated the HP proMastocyte (HPM) cell line and characterized. HPS-1 and idiopathic pulmonary fibrosis (IPF) alveolar interstitium showed numerous HuMCs; HPS-1 dermal mast cells exhibited abnormal granules when compared to healthy controls. HPS-1 HuMCs showed increased CD63, CD203c and reduced mediator release following FcɛRI aggregation when compared with normal HuMCs. HPM cells also had the duplication defect, expressed FcɛRI and intracytoplasmic proteases and exhibited less mediator release following FcɛRI aggregation. HPM cells constitutively released IL-6, which was elevated in patients' serum, in addition to IL-8, fibronectin-1 (FN-1) and galectin-3 (LGALS3). Transduction with HPS1 rescued the abnormal HPM morphology, cytokine and matrix secretion. Microarray analysis of HPS-1 HuMCs and non-transduced HPM cells confirmed upregulation of differentially expressed genes involved in fibrogenesis and degranulation. Cultured HPS-1 HuMCs appear activated as evidenced by surface activation marker expression, a decrease in mediator content and impaired releasibility. The near-normalization of constitutive cytokine and matrix release following rescue by HPS1 transduction of HPM cells suggests that HPS-1 HuMCs may contribute to pulmonary fibrosis and constitute a target for therapeutic intervention.

Project description:RationalePulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown.ObjectivesTo assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism.MethodsRats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling.Measurements and main resultsIn Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1.ConclusionsElafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.

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Pulmonary hypertension and metabolic syndrome: Possible connection, PPAR? and Caveolin-1.

Publications

Pulmonary hypertension and metabolic syndrome: Possible connection, PPARγ and Caveolin-1.

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