Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin-Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling

Abstract

The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

“…Our laboratory has recently found evidence to support a positive role for the attenuation of NAD(P)H oxidase production of oxidative stress in the myocardium and cardiac remodeling utilizing mineralocorticoid receptor blockade with low-dose spironolactone in the Ren2 model of hypertension, oxidative stress, and IR [176]. Further, our current studies demonstrate abrogation of many islet and pancreatic structural and functional changes in the Ren2 model [50].…”

NOX Enzymes and Pulmonary Disease

“…Currently limited published studies are available on in vivo roles for NOX4 in lung fibrosis; however, studies in kidney fibrosis (12,89,120,143), vascular-remodeling=fibrosis associated with chronic hypertension (4), cardiac fibrosis (39, 112,139), and pancreatic fibrosis (75) suggest a role for the NOX4 isoform in the fibrogenic process. Other NOX isoforms that are reported to contribute to tissue fibrosis in nonpulmonary organ systems include NOX1 (4,75,112,139) and NOX2 (67,75,89,112,143).…”

“…Other NOX isoforms that are reported to contribute to tissue fibrosis in nonpulmonary organ systems include NOX1 (4,75,112,139) and NOX2 (67,75,89,112,143). A p47 phox -requiring NOX isoform is required for the development of fibrosis in a murine lung-injury model that is inflammation dependent, and the observed protection in p47 phoxÀ=À mice is associated with enhanced neutrophilic inflammation and matrix metalloproteinase (MMP)-9 activity (70).…”

“…A p47 phox -requiring NOX isoform is required for the development of fibrosis in a murine lung-injury model that is inflammation dependent, and the observed protection in p47 phoxÀ=À mice is associated with enhanced neutrophilic inflammation and matrix metalloproteinase (MMP)-9 activity (70). Significant crosstalk occurs between the reninangiotensin-aldosterone system and TGF-b1 in organ fibrosis (130,147), and this effect is, at least in part, mediated by induction=activation of NOX1, NOX2, NOX4, or a combination of these (4,12,112,120,139,143).…”

Renin-Angiotensin-Aldosterone System and Replicative Cellular Senescence: Their Interaction During the Vascular Ageing

“…Избыток альдостерона способствует ремодели-рованию сердечно-сосудистой ткани за счет усиления синтеза коллагена, что ве-дет к повышению жесткости сосуди-стой стенки, гипертрофии миокарда левого желудочка и фиброзу почек [20]. На экспериментальных моделях грызу-нов с избытком АТII и альдостерона было продемонстрировано, что бло-када минералокортикоидных рецепто-ров ослабляет окислительный стресс в тканях сердца и почек за счет сокраще-ния NAD (P) H-оксидазы и приводит к уменьшению выраженности интерсти-циального фиброза, ремоделирования тканей и признаков гипертрофии [22]. Тканевая РААС Одним из наиболее значимых достижений в из-учении РААС в последние два десятилетия стало от-крытие местной или тканевой РААС.…”