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 Article Swipe
Yongneng Zhang
,
Sotirios Zervopoulos
,
Aristeidis E. Boukouris
,
Maria Areli Lorenzana‐Carrillo
,
Bruno Saleme
,
Linda Webster
,
Yongsheng Liu
,
Alois Haromy
,
Seyed Amirhossein Tabatabaei Dakhili
,
John R. Ussher
,
Gopinath Sutendra
,
Evangelos D. Michelakis
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1161/jaha.120.020451
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1161/jaha.120.020451
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.
Related Topics
Concepts
SIRT3
Medicine
Insulin resistance
Internal medicine
Pulmonary artery
Single-nucleotide polymorphism
Endocrinology
Mitochondrion
Pulmonary hypertension
Type 2 diabetes
Diabetes mellitus
Cardiology
Gene
Biology
Genetics
Sirtuin
Genotype
Acetylation
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1161/jaha.120.020451
- https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.020451
- OA Status
- gold
- Cited By
- 15
- References
- 42
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3208690493
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W3208690493Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1161/jaha.120.020451Digital Object Identifier
- Title
-
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 GenesWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2021Year of publication
- Publication date
-
2021-10-30Full publication date if available
- Authors
-
Yongneng Zhang, Sotirios Zervopoulos, Aristeidis E. Boukouris, Maria Areli Lorenzana‐Carrillo, Bruno Saleme, Linda Webster, Yongsheng Liu, Alois Haromy, Seyed Amirhossein Tabatabaei Dakhili, John R. Ussher, Gopinath Sutendra, Evangelos D. MichelakisList of authors in order
- Landing page
-
https://doi.org/10.1161/jaha.120.020451Publisher landing page
- PDF URL
-
https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.020451Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.ahajournals.org/doi/pdf/10.1161/JAHA.120.020451Direct OA link when available
- Concepts
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SIRT3, Medicine, Insulin resistance, Internal medicine, Pulmonary artery, Single-nucleotide polymorphism, Endocrinology, Mitochondrion, Pulmonary hypertension, Type 2 diabetes, Diabetes mellitus, Cardiology, Gene, Biology, Genetics, Sirtuin, Genotype, AcetylationTop concepts (fields/topics) attached by OpenAlex
- Cited by
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15Total citation count in OpenAlex
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2025: 5, 2024: 2, 2023: 4, 2022: 3, 2021: 1Per-year citation counts (last 5 years)
- References (count)
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42Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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