PKC delta Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function

Author(s)

Lu, Qing ^[1] ; Davel, Ana P. ^[2] ; McGraw, Adam P. ^[1] ; Rao, Sitara P. ^[1] ; Newfell, Brenna G. ^[1] ; Jaffe, Iris Z. ^[1]

Affiliation

^[1] Tufts Med Ctr, Mol Cardiol Res Inst, 800 Washington St, Box 80, Boston, MA 02111 - USA

^[2] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: Endocrinology; v. 160, n. 9, p. 2101-2114, SEP 2019.
• Web of Science Citations: 0

Abstract

Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that Angll activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that Angll induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. Angll activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-delta (PKC delta) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKC delta in SMCs prevented Angll-mediated MR acti vation, whereas knocking down of MR blocked both aldosterone- and Angll-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKC delta form a complex in SMCs that is enhanced by Angll treatment in association with increased serine phosphorylation of the MR N terminus. Angll increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of Angll on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the Angll-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKC delta inhibitor rottlerin. These data demonstrate that Angll activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKC delta-dependent manner. This new mechanism may contribute to synergy between MR and Angll in driving SMC dysfunction and to the cardiovascular benefits of MR and Angll receptor blockade in humans. (AU)

• FAPESP's process: 14/26192-6 - Role of endothelial mineralocorticoid receptor on the endothelial dysfunction and oxidative stress in cardiovascular diseases
• Grantee: Ana Paula Couto Davel
• Support Opportunities: Scholarships abroad - Research