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17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
- Source :
- The Journal of clinical investigation, vol 131, iss 6, J Clin Invest
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
Abstract
- Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.
- Subjects :
- Male
0301 basic medicine
Pulmonology
Molecular biology
Estrogen receptor
Cardiovascular
Medical and Health Sciences
Mice
0302 clinical medicine
Models
Ventricular Function
Sex hormones
Myocytes, Cardiac
Lung
Mice, Knockout
Estradiol
Models, Cardiovascular
Pulmonary
General Medicine
Apelin
Mutant Strains
Right
030220 oncology & carcinogenesis
Hypertension
Female
Cardiac
Research Article
Agonist
medicine.medical_specialty
Cardiotonic Agents
medicine.drug_class
Knockout
Hypertension, Pulmonary
Immunology
Heart failure
Bone Morphogenetic Protein Receptors, Type II
Type II
Rats, Mutant Strains
03 medical and health sciences
Rare Diseases
Downregulation and upregulation
Vascular Biology
In vivo
Internal medicine
medicine
Animals
Humans
Myocytes
Animal
business.industry
Estrogen Receptor alpha
Endothelial Cells
Bone Morphogenetic Protein Receptors
medicine.disease
Estrogen
Pulmonary hypertension
Rats
BMPR2
Disease Models, Animal
030104 developmental biology
Endocrinology
Disease Models
Ventricular Function, Right
business
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....d7d9cef2749864fb6eb97bb7641427ae