ANG II-induced cardiac molecular and cellular events: role of aldosterone

Abstract

Chronic elevation of circulating ANG II is associated with cardiac remodeling in patients with hypertension and heart failure. The underlying mechanisms, however, are not completely defined. Herein, we studied ANG II-induced molecular and cellular events in the rat heart as well as their links to the redox state. We also addressed the potential contribution of aldosterone (ALDO) on ANG II-induced cardiac remodeling. In ANG II-treated rats, and compared with controls, we found: 1) the expression of proinflammatory/profibrogenic mediators was significantly increased in the perivascular space and at the sites of microscopic injury in both ventricles; 2) macrophages and myofibroblasts were primary repairing cells at these sites, together with increased fibrillar collagen volume; 3) apoptotic macrophages and myofibroblasts were evident at the same sites; 4) NADPH oxidase (gp91 phox ) was significantly enhanced at these regions and primarily expressed by macrophages, whereas superoxide dismutase and catalase levels remained unchanged; 5) plasma 8-isoprostane levels were significantly increased; and 6) blood pressure was significantly elevated. Losartan treatment completely prevented cardiac oxidative stress as well as molecular/cellular responses and normalized blood pressure. Spironolactone treatment partially suppressed the cardiac inflammatory/fibrogenic responses and redox state. Thus chronic elevation of circulating ANG II is accompanied by a proinflammatory/profibrogenic phenotype involving vascular and myocardial remodeling in both ventricles. Enhanced reactive oxygen species production at these sites and increased plasma 8-isoprostane indicate the involvement of oxidative stress in ANG II-induced cardiac injury. ALDO contributes, in part, to ANG II-induced cardiac molecular and cellular responses. cardiac remodeling; angiotensin II; aldosterone; oxidative stress; rats AS A CIRCULATING HORMONE, endocrine properties of ANG II are integral to the regulation of blood pressure and volume homeostasis. However, chronic elevation of circulating ANG II, such as occurs with congestive heart failure and hypertension, is inappropriate and has adverse consequences. For example, such neurohormonal activation has been related to a diverse number of vascular diseases, including atherosclerotic coronary artery disease, cardiac perivascular fibrosis, and diabetes (6,8). An important vascular effect of ANG II is its induction of oxidative stress and a proinflammatory phenotype. Type I ANG II (AT 1 ) receptor blockade can prevent the unfavorable vascular effects by ANG II through hypertension-dependent and -independent mechanisms (1,18,22). Our previous studies have demonstrated that, in addition to vascular remodeling, elevation of circulating ANG II levels also leads to extensive microscopic myocardial repair/remodeling in both left and right ventricles in rats (21, 22). However, ANG II-induced myocardial molecular/cellular events and their relation to oxidative stress have not been fully explored.ANG II stimulates aldosterone ...

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

“…ANG II infusion in mice also reduces the total SOD activity in plasma, aorta and kidney cortex as well as the mRNA and protein expression for EC-SOD [102]. Compared to the normal rat heart, gp91 phox mRNA is largely increased within the perivascular and microscopic injury in both ventricles in ANG II-treated rats and cells expressing gp91 phox at these sites were primarily inflammatory cells; cardiac Mn-SOD and catalase protein levels, however, remain unchanged in ANG II-infused rats [103]. In ANG IIinfused mice the aorta mRNA and protein expression of EC-SOD as well as the EC-SOD activity is increased, while the CuZn-SOD protein expression is unchanged [104].…”

“…In ANG II-infused rat kidney a 50% decrease in Mn-SOD activity is observed [108], while Chabrashvili et al [101] reported an increased mRNA expression of Mn-SOD in the kidney cortex of ANG IItreated rats. An unchanged Mn-SOD protein expression is found in cardiac [103] and kidney [108] tissue of ANG IIinfused rats, while a reduced renal Mn-SOD protein level is found in ANG II-treated rats [109]. In ANG II-infused mice, the aortic protein level Mn-SOD is unchanged, but declines in extracellular SOD deficient mice [110].…”

Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance

“…Both cardiomyocytes and fibroblasts express MRs with high affinity for both corticosterone and aldosterone (110,181,157). The inflammatory effects of coricosterone and aldosterone in the heart are partly mediated by an interaction with the RAAS as well as effects directly mediated through MR activation (39,55,56,73,90,167,168,170,196,238). For example, in rats treated with aldosterone and high dietary salt, the AT 1 R expression and ventricular density of the AT 1 R have been observed to increase (90).…”

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

“…After exposure, the film was developed and sections were stained with hematoxylin and eosin. Quantitation of mRNA optical density was performed using a computer image analysis system (NIH Image, 1.60) (23).…”