OR02-1 Smooth Muscle Cell Mineralocorticoid Receptors Regulate Vascular L-Type Calcium Channels Via microRNA-155 to Contribute to Aging-Associated Hypertension

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR02-Renin-Angiotensin-Aldosterone - Bench to Bedside
Friday, April 1, 2016: 11:45 AM-1:15 PM
Presentation Start Time: 11:45 AM
Room 156 (BCEC)
Jennifer DuPont*1, Amy McCurley1, Joseph C McCarthy1, Shawn B Bender2, Wendy Baur1, Michael Hill3 and Iris Z Jaffe1
1Tufts Medical Center, Boston, MA, 2Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, 3University of Missouri, Columbia, MO
Blood pressure (BP) rises with age, making hypertension (HTN) the most prevalent cardiovascular disease risk-factor. We found that mice with SMC-specific deletion of the mineralocorticoid receptor (MR-KO) lack the aging-associated rise in BP. Vascular micro-RNA expression profiling revealed that miR-155 is an aging-associated miR that is modulated by SMC-MR. Ingenuity pathway analysis identified Cav1.2, the pore forming subunit of the L-type calcium channel (LTCC), as a potential target of miR-155. We hypothesize that SMC-MR contributes to BP regulation with aging by regulating vascular L-type calcium channel (LTCC) expression/function via regulation of miR-155. Vascular miR-155 expression declines with age in MR-intact mice (p<0.05 vs. young MR-intact) and is increased in aged MR-KO (p<0.05 vs. MR-intact). Luciferase reporter assays reveal that MR significantly decreased miR-155 promoter activity in a dose dependent manner (p<0.05), suggesting that MR negatively regulates the transcription of miR-155. Overexpression of miR-155 in mouse SMC reduced Cav1.2 expression by 45% (p<0.05 vs. ctrl). Patch clamp studies on freshly dispersed mesenteric resistance vessel (MRV) SMC reveal reduced LTCC current density in SMC from aged MR-KO mice (p<0.05 vs. MR-intact) with no difference in SMC from young mice. Fura-2 photometry studies similarly reveal decreased MRV Ca flux in response to BayK (LTCC agonist) only in aged MR-KO (p<0.05 vs. MR-intact). Vascular contraction to BayK is also blunted in aged MR-KO MRV (p<0.05 vs. MR-intact). RNA expression of Cav1.2 is reduced by 60% in aged MR-KO vs. MR-intact MRV (p<0.05). These data suggest that SMC-MR contributes to HTN through regulating Cav1.2 expression/function, via transcriptional repression of miR-155. These results enhance our basic understanding of BP control with aging, and provide support for innovative therapeutic targets to treat aging-associated HTN.

Nothing to Disclose: JD, AM, JCM, SBB, WB, MH, IZJ

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo

Sources of Research Support: Supported by NIH Grant HL095590-05 (IZJ), American Heart Association Grant 15POST21300000 (JJD), and VA Grant VA CDA-2 IK2 BX002030 (SBB).