Angiotensin II (AngII) is a potent vasoconstrictor and stimulator of pathologic cardiovascular remodeling. Bradykinin, has been shown to exert opposing effects when acting at its B2 receptor. However, the impact of B1 receptor stimulation on cardiovascular remodeling is less clear. In the kidney, B1 receptor antagonism has been shown to have reno‐protective effects in a model of obstructive nephropathy, while the impact on cardiac remodeling is equivocal. It has been shown to both induce and attenuate pathological cardiac remodeling. Activation of the B1 receptor and the Angiotensin II AT1 receptor have both been shown to increase oxidative stress and mitogen activated‐protein kinases (MAPK). Moreover, B1 receptor antagonism has been shown to offset AngII‐induced Erk phosphorylation and reactive oxygen species production. The goal of the present study was to determine the impact of B1 receptor antagonism in AngII‐infused rats on expression of reactive oxygen species (ROS) enzymes and MAPKs p38 and ERK1/2 in the left ventricle (LV) and kidney. Adult male Sprague Dawley Rats received a four‐week treatment of either saline or AngII (200ng/kg per min, s.c.), B1 receptor antagonist R‐954 (400 μg/kg per day, s.c.), or combined R‐954 + AngII. Mean arterial pressure (MAP) was measured via carotid catheter in anesthetized rats. Kidneys and hearts were excised and protein expression of the pro‐/anti‐oxidants (NOX2, SOD1, SOD2, and catalase) as well as phosphorylated and total p38 and p42/44 were measured by Western Blot. Relative to vehicle, MAP increased by 43% (p<0.05) in AngII treated rats, and by 64% (p<0.05) in AngII+R rats. LV/BW was significantly increased, relative to vehicle in AngII (30%) and AngII+R (31%) rats. In both the left ventricle and kidney, there were no notable effects on the expression of NOX2, SOD2, catalase, or pERK 1/2. In the heart, AngII decreased expression of SOD1 (−27% vs. vehicle, p=0.066) and this was offset by R‐954 (+7% vs. vehicle). In the kidney, AngII also decreased expression of SOD1 (−26% vs. vehicle, p=0.082) however this was not impacted by concomitant R‐954 (−44% vs. vehicle). In the heart, AngII treatment tended to increase p‐p38/p38 (+8.24%) and this was enhanced by combined treatment with R‐954 (+31%, p<0.05). There was no notable impact of treatment on p‐p38/ p38 in kidney. Taken together, the present findings demonstrate that while bradykinin B1 receptor antagonism did not impact AngII‐induced left ventricular remodeling, there appeared to be synergistic and antagonistic effects of this combination in the left ventricle. Namely, combination of angiotensin plus the B1R antagonist resulted in enhanced phosphorylation of p38, but attenuation of the AngII‐mediated reduction in SOD1 in the left ventricle. In contrast, there was no notable effect of B1R antagonism on these AngII‐mediated effects in the kidney. Future studies will investigate the apparent tissue‐specific cross‐talk between angiotensin and bradykinin receptor‐mediated signaling pathways.Support or Funding InformationAPS Undergraduate Summer Research Fellowship University of Arizona, College of Medicine ‐ Phoenix Springboard GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Following washout of angiotensin converting enzyme inhibitor (ACEi) treatment in hypertensive rats (SHR), there is an increase in the proportion of homeostatic cardiac fibroblasts (CFs) characterized by a less fibrogenic gene profile. The present study investigated the impact of this shift in CFs on subsequent Ang II-induced oxidative stress and fibrogenic responses in the left ventricle (LV). Male and female SHRs (11 wk old) underwent a 6-week treatment scheme: 2-week ACEi (enalapril, 30mg/kg/day) or vehicle treatment, followed by a 2-week washout period, and then a 2-week Ang II (400ng/kg/min, s.c.) or vehicle infusion (n=5-11/group/sex). RT-qPCR for collagens and immunoblotting for LOX, Postn, OPN, NOX2, SOD2, and catalase was performed. In males, Ang II-induced increases in ColI, III, and IV expression were significantly attenuated by prior ACEi. While in females, Ang II significantly increased the expression of ColI and III similarly, regardless of prior ACEi treatment; highlighting a sex-specific impact of ACEi. After Ang II infusion, both Postn and LOX are reduced in LV of male and female SHR previously treated with an ACEi - suggesting reduced collagen cross-linking. Oxidative stress induced by NOX2 has been linked to OPN in fibrotic tissue. Ang II-induced increases in NOX2 are attenuated in LV of both sexes, while OPN is only reduced in females previously treated with an ACEi. NOX2 is significantly positively correlated with OPN in males only suggesting a sex-specific link between OPN and oxidative stress. Antioxidant (SOD2, catalase) levels were positively correlated to NOX2 in females, but not males. This suggests that females more efficiently neutralize oxidative stress than males - regardless of prior ACEi. Taken together, the persistent genomic and phenotypic changes in CFs following transient ACEi render the heart resistant to future fibrotic and oxidative effects of Ang II, but the mechanisms of protection may differ by sex. Collectively, these data reveal that there are sex-specific processes that govern collagen production vs. cross-linking and oxidative stress. Future studies will elucidate the mechanistic underpinnings of sex-specific cellular memory following transient ACEi with a goal of identifying novel therapeutic targets.
Hypertension promotes fibrotic cardiac remodeling that involves oxidative stress and inflammation that contribute to heart failure. Transient angiotensin converting enzyme inhibitor (ACEi) treatment in male hypertensive rats (SHR) produces persistent changes in the left ventricle (LV) that render it resistant to future fibrosis and inflammation. Oxidative stress produced by NADPH oxidase (NOX) enzymes is linked to angiotensin II (Ang II)‐mediated fibrotic signaling. Ang II also promotes secretion of macrophage‐recruiting cytokines including monocyte chemoattractant protein 1 (MCP1) which can perpetuate oxidative stress. Thus the present study investigated the impact of transient ACEi‐induced cardio‐protection on subsequent Ang II‐induced inflammatory and oxidative stress responses. After a 2‐week ACEi treatment (enalapril, 30mg/kg/day) followed by a 2‐week washout period male and female SHRs (11 wk old) were infused with Ang II (400ng/kg/min, s.c.) or vehicle (saline, n=5‐11/group/sex) for 2 weeks. At time of euthanasia, a mid‐myocardial section was fixed and paraffin embedded and remaining LV tissue was collected for protein, RNA and DNA extraction. LV macrophage infiltration was determined histologically by staining for ED‐1. MCP1 gene expression was evaluated by RTqPCR, and pro‐oxidants (NOX2 and NOX4) and antioxidants (catalase and superoxide dismutase 2; SOD2) were measured by immunoblotting. Oxidative DNA damage was quantified using an 8‐hydroxy‐2’‐deoxyguanosine (8‐OHdG) ELISA. Cardiac MCP1 gene expression was increased by Ang II in both sexes with no impact of transient ACEi. However, Ang II induced LV macrophage infiltration (ED‐1) in males only which was attenuated by prior transient ACEi. LV NOX2 was increased by Ang II and attenuated by prior transient ACEi in both sexes. NOX4 was reduced in females previously treated with an ACEi, but not males. The antioxidant, catalase, was increased by Ang II in both sexes, but attenuated by transient ACEi in females only. Further, both catalase and SOD2 were positively correlated to NOX2 in females, but not males. This suggests that Ang II‐induced pro‐oxidant responses may be more tightly coupled with antioxidant responses in females. DNA damage as measured by 8‐OHdG was not significantly impacted by Ang II in males or females. However 8‐OHdG was reduced in males previously treated with an ACEi suggesting that an alternative antioxidant mechanism may be active in males previously treated with an ACEi. At this dose and duration of Ang II there is not significant oxidative DNA damage, but MCP1 and pro‐oxidants are increased in both sexes. Males exhibit greater macrophage infiltration, while females exhibit greater antioxidant responses; both of which are prevented by prior transient ACEi. In conclusion, there are sex‐specific inflammatory and oxidative stress responses to Ang II and transient ACEi that may impact future cardiac remodeling. Current and future studies will aim to identify mechanisms involved in transient ACEi‐mediated cardio‐protection and how these ...
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