title: Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation.
abstract: Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine(473) phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine(136) and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.
authors.affiliation: Department of Medicine, Diabetes and Cardiovascular Center of Excellence, University of Missouri-Columbia, Columbia, MO 65212, USA.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wei
authors.forename: Adam T
authors.initials: AT
authors.lastname: Whaley-Connell
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.forename: Jenna
authors.initials: J
authors.lastname: Rehmer
authors.forename: Nathan
authors.initials: N
authors.lastname: Rehmer
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Patel
authors.forename: Melvin
authors.initials: M
authors.lastname: Hayden
authors.forename: Vincent
authors.initials: V
authors.lastname: DeMarco
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: Jamal A
authors.initials: JA
authors.lastname: Ibdah
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494821:Bad protein, rat; D000451:Mineralocorticoid Receptor Antagonists; D017382:Reactive Oxygen Species; C535029:Ren2 protein, rat; D051025:bcl-Associated Death Protein; D013148:Spironolactone; D000450:Aldosterone; D045304:Cytochromes c; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin