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.
In response to hypertensive stimuli, like angiotensin II (AngII), cardiac fibroblasts (CFs) transform into an activated phenotype, which triggers increased collagen deposition and pro‐inflammatory signals. Transforming growth factor beta 1 (TGF‐β1) and reactive oxygen species are important modulators of AngII‐induced cardiac fibrosis and CF activation. The extent to which the AngII‐induced changes in CF phenotype persist in the absence of ongoing stimulation is not known. The objective of the present study was to determine the persistent impact of chronic AngII infusion on CF phenotype. Specifically, we performed an in vitro characterization of CFs isolated from rats chronically treated with AngII (in vivo) or saline (vehicle) and investigated acute (in vitro) responses to AngII thereafter. Adult male SD rats were administered AngII (200 ng/kg/min) or saline for 4 weeks. In half of the rats in each group, we measured mean arterial pressure (MAP), weighed the left ventricle (LV), and fixed a section of LV for assessment of collagen deposition (Sirius Red). In remaining rats, CFs were isolated and passaged to P1. CFs were treated in vitro with AngII (1uM) or vehicle for 72 hr. TGF‐β1 and monocyte chemoattractant protein 1 (MCP‐1) were assessed in culture media. Expression of pro‐/anti‐oxidant proteins NADPH oxidase 2 (Nox2), catalase and superoxide dismutase 1 (SOD1) were determined by western blot. Ang II increased MAP (43%, p<0.05), LV/BW (30%, p<0.05), and LV collagen deposition. TGF‐β1 release was not different from CFs isolated from saline vs. AngII infused rats. However, in vitro incubation with AngII significantly increased TGF‐β1 secretion in all CFs. CFs isolated from AngII‐infused rats secreted elevated levels of MCP‐1 (p<0.05), when compared to control CFs. MCP‐1 levels were not further modified by acute AngII treatment. Basal expression of Nox2, SOD1, and catalase was similar between CFs isolated from control vs. AngII‐infused rats. Acute AngII tended to increase Nox2 expression in CFs isolated from vehicle and AngII‐treated rats, whereas AngII only increased SOD1 expression (46%, p<0.05) in CFs from AngII‐infused rats. In vitro stimulation with AngII tended to increase catalase in CFs isolated from control rats, but reduced (20%, p<0.05) expression in CFs isolated from AngII infused rats. Taken together, these data demonstrate that CFs isolated from an actively remodeling myocardium continue to secrete elevated levels of MCP‐1, but not TGF‐β1, in vitro. Moreover, CFs from AngII‐infused rats displayed altered expression of antioxidant enzymes following AngII in vitro, which may play a role in worsened inflammatory signaling and resultant pro‐fibrotic activity. Future studies will further elucidate the fibrotic and inflammatory characteristics of CFs from the remodeling myocardium and determine the extent to which this persistent phenotype alters the future responsiveness to a pathogenic stimulus.Support or Funding InformationSpringboard Grant, UA College of Medicine – PhoenixThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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