| Autor: |
Fredette NC; Department of Pathology, Immunology and Experimental Medicine, University of Florida College of Medicine, Gainesville, Florida., Malik E; Department of Pathology, Immunology and Experimental Medicine, University of Florida College of Medicine, Gainesville, Florida., Mukhtar ML; Department of Mechanical & Aerospace Engineering, University of Florida Herbert Wertheim College of Engineering, Gainesville, Florida., Prossnitz ER; Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico., Terada N; Department of Pathology, Immunology and Experimental Medicine, University of Florida College of Medicine, Gainesville, Florida. |
| Jazyk: |
angličtina |
| Zdroj: |
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2020 Nov 01; Vol. 319 (5), pp. C825-C838. Date of Electronic Publication: 2020 Aug 12. |
| DOI: |
10.1152/ajpcell.00350.2019 |
| Abstrakt: |
Hypertension (HTN) is a polyfactorial disease that can manifest severe cardiovascular pathologies such as heart failure or stroke. Genome-wide association studies (GWAS) of HTN indicate that single-nucleotide polymorphisms (SNPs) contribute to increased risk for HTN and resistance to some HTN drug regimens (Hiltunen TP et al., J Am Heart Assoc 4: e001521, 2015; Le MT et al., PLoS One 8: e52062, 2013; McDonough CW et al., J Hypertens 31: 698-704, 2013; Vandell AG et al., Hypertension 60: 957-964, 2012). However, cellular mechanistic insights of such SNPs remain largely unknown. Using a bank of induced pluripotent stem cells (iPSCs) derived from patients with HTN and CRISPR/Cas9-mediated gene-editing approach, we investigated the effects of a female HTN risk-associated SNP (rs1154431) of the G protein-coupled estrogen receptor (GPER) (Bassuk SS, Manson JE., Clin Chem 60: 68-77, 2014) in vascular endothelial cells. Although GPER1 deletion reduced endothelial nitric oxide synthase (eNOS) activation in iPSC-derived endothelial cells (iECs), the polymorphism itself did not significantly affect eNOS and NO production in a comparison of isogenic hemizygous iECs expressing either normal (P16) or HTN-associated (L16) GPER. Interestingly, we demonstrate for the first time that GPER plays a role in regulation of adhesion molecule expression and monocyte adhesion to iECs. Moreover, the L16 iECs had higher expression of inflammation genes than P16 iECs, implying that the risk variant may affect carrier individuals through increased inflammatory activity. This study further indicates that iPSCs are a useful platform for exploring mechanistic insights underlying hypertension GWAS endeavors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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