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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Endres, Bradley T. Weinberg, Brian D. Moreno, Carol Priestley, Jessica R. C. Palygin, Oleg Flister, Michael J. Staruschenko, Alexander Grzybowski, Michael Jacob, Howard J. Hoffman, Matthew J. Lombard, Julian H. Geurts, Aron M. |
| Description | Author Affiliation: Endres BT ( Departments of Physiology and Human and Molecular Genetics Center, and.); Priestley JR ( Departments of Physiology and.); Palygin O ( Departments of Physiology and.); Flister MJ ( Departments of Physiology and Human and Molecular Genetics Center, and.); Hoffman MJ ( Departments of Physiology and.); Weinberg BD ( Departments of Physiology and.); Grzybowski M ( Departments of Physiology and Human and Molecular Genetics Center, and.); Lombard JH ( Departments of Physiology and.); Staruschenko A ( Departments of Physiology and.); Moreno C ( Departments of Physiology and Human and Molecular Genetics Center, and.); Jacob HJ ( Departments of Physiology and Human and Molecular Genetics Center, and Pediatrics.); Geurts AM ( Departments of Physiology and Human and Molecular Genetics Center, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226 ageurts@mcw.edu.); |
| Abstract | PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zinc-finger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 35 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Blood Pressure Genetics Carrier Proteins Hypertension, Renal Sodium Chloride Pharmacology Albuminuria Pathology Physiopathology Animals Physiology Calcium Metabolism Cardiac Output Disease Models, Animal Endothelial Cells Genome-Wide Association Study Mesenteric Arteries Nitric Oxide Rats, Inbred Dahl Rats, Mutant Strains Vascular Resistance Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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