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A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

ABSTRACT: Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGF?)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT1R, and AT2R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT1R and AT2R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.

SUBMITTER: Lyu L

PROVIDER: S-EPMC4988239 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

Lyu Linmao L Wang Hui H Li Bin B Qin Qingyun Q Qi Lei L Nagarkatti Mitzi M Nagarkatti Prakash P Janicki Joseph S JS Wang Xing Li XL Cui Taixing T

Journal of molecular and cellular cardiology 20151020 Pt B

Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via ...[more]

PMID: 26497614

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Project description:Background Renin-angiotensin system blockers (RASBs) have well-validated benefit in patients with hypertension, coronary artery disease, and left ventricular systolic dysfunction. Their use in the perioperative period, however, has been controversial, including in patients undergoing cardiac surgery, who often have a strong indication for their use. In the current study, we explore the impact of RASB use with 30-day and 1-year mortality after cardiac surgery. Methods and Results The Veterans Affairs Surgical Quality Improvement Program and Corporate Data Warehouse were data sources for this retrospective cohort study. A total of 37 197 veterans undergoing elective coronary artery bypass grafting and or valve repair or replacement over a 10-year period met inclusion criteria and were stratified into 4 groups by preoperative exposure (preoperative exposure versus no preoperative exposure) and postoperative continuing exposure (current exposure versus no current exposure) to RASBs. After adjusting for all baseline covariates, the preoperative exposure/current exposure group had lower 30-day and 1-year mortality than the preoperative exposure/no current exposure (30-day hazard ratio [HR], 0.25; 95% CI, 0.19-0.33 [P<0.001] and 1-year HR, 0.40; 95% CI, 0.33-0.48 [P<0.001] or no preoperative exposure/no current exposure (30-day HR, 0.44; 95% CI, 0.32-0.60 [P<0.001] and 1-year HR, 0.72; 95% CI, 0.62-0.84 [P<0.001] groups. The no preoperative exposure/current exposure group had significantly lower 30-day (HR, 0.31; 95% CI, 0.14-0.71 [P=0.006]) and 1-year (HR, 0.64; 95% CI, 0.53-0.77 [P<0.001]) mortality than the no preoperative exposure/no current exposure group. Conclusions Continuation of preoperative RASBs and initiation before discharge is associated with decreased mortality in veterans undergoing cardiac surgery. Given these findings, continuation of preoperative RASBs or initiation in the early postoperative period should be considered in patients undergoing cardiac surgery.

Project description:AimsKlotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition.Methods and resultsA total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; Pinteraction < 0.01).ConclusionsLow Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

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A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

Publications

A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes.

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