scholarly journals Correction to: SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes

2021 ◽  
Keyword(s):  
Type 2 Diabetes ◽  
Pulmonary Arterial Hypertension ◽  
Mouse Model ◽  
Arterial Hypertension ◽  
Uncoupling Protein ◽  
Mitochondrial Proteins ◽  
Uncoupling Protein 2 ◽  
Genes Encoding ◽  
Pulmonary Arterial

scholarly journals SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes

2021 ◽  
Author(s):  
Yongneng Zhang ◽  
Sotirios D. Zervopoulos ◽  
Aristeidis E. Boukouris ◽  
Maria Areli Lorenzana‐Carrillo ◽  
Bruno Saleme ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Pulmonary Arterial Hypertension ◽  
Mouse Model ◽  
Pulmonary Artery ◽  
Uncoupling Protein ◽  
Wild Type ◽  
Double Knockout ◽  
Pulmonary Arterial

Background Isolated loss‐of‐function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10‐year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose‐dependent manner), along with insulin resistance, compared with wild‐type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild‐type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.

scholarly journals Schistosomiasis Pulmonary Arterial Hypertension

2020 ◽  
Vol 11 ◽  
Author(s):  
Jean Pierre Sibomana ◽  
Aloma Campeche ◽  
Roberto J. Carvalho-Filho ◽  
Ricardo Amorim Correa ◽  
Helena Duani ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Heart ◽  
Systematic Screening ◽  
Pulmonary Vasodilators ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.

scholarly journals Association of 45-bp ins/del polymorphism of uncoupling protein 2 (UCP2) and susceptibility to nonalcoholic fatty liver and type 2 diabetes mellitus in North-west of Iran

2020 ◽  
Author(s):  
Salehe Rezapour ◽  
Shiva Ahdi Khosroshahi ◽  
Hadi Farajnia ◽  
Fatemeh Mohseni ◽  
Manouchehr Khoshbaten ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Fatty Liver ◽  
Uncoupling Protein ◽  
P Value ◽  
Uncoupling Protein 2 ◽  
Genotype Distribution ◽  
Healthy Controls

Abstract Objective: Uncoupling protein 2 (UCP2) plays a crucial role in energy homeostasis via regulation of insulin secretion, free fatty acid concentrations, and lipid metabolism. This study aimed to investigate the association of 45-bp ins/del polymorphism of UCP2 with susceptibility to NAFLD (Non Alcoholic Fatty Liver Disease) and T2DM (Type 2 Diabetes Mellitus). DNA was extracted from the white blood cells of the subjects, and the gene polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In this study, 72 patients with NAFLD, 71 healthy individuals as control, 80 patients with T2DM, and 77 healthy controls were enrolled in the study.Results: A higher prevalence of insertion/insertion genotype was observed in T2DM patients compared to the controls (p- value˂ 0.05). But, there was no difference in genotype distribution between NAFLD patients and controls (p-value> 0.05). NAFLD patients with D/D, D/I genotype had higher triglyceride, ALT, and AST levels; however, their HDL levels were lower than healthy controls. Patients with T2DM with D/D or D/I genotype also had significantly higher fasting serum glucose (FSG). While we found an association between the 45bp I/D polymorphism in 3ʹUTR of UCP2 and T2DM, no any correlation between this polymorphism and NAFLD was identified.

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