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
| Autor: | John R. Ussher, Yongsheng Liu, Sotirios Zervopoulos, Aristeidis E. Boukouris, Seyed Amirhossein Tabatabaei Dakhili, Yongneng Zhang, Gopinath Sutendra, Maria Areli Lorenzana-Carrillo, Alois Haromy, Evangelos D. Michelakis, Linda Webster, Bruno Saleme |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
SIRT3 vascular remodeling Type 2 diabetes Mitochondrion Polymorphism Single Nucleotide Severity of Illness Index Mice Insulin resistance Right ventricular hypertrophy Sirtuin 3 Internal medicine medicine.artery medicine Diseases of the circulatory (Cardiovascular) system Animals Humans Uncoupling protein Uncoupling Protein 2 Prospective Studies Pulmonary Arterial Hypertension business.industry vascular disease medicine.disease plexogenic arteriopathy mitochondria Transplantation Disease Models Animal Treatment Outcome Endocrinology Diabetes Mellitus Type 2 RC666-701 Pulmonary artery Insulin Resistance Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 23 (2021) |
| ISSN: | 2047-9980 |
| DOI: | 10.1161/jaha.120.020451 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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