Francisco Olivares-Silva1, Nicole De Gregorio2, Jenaro Espitia-Corredor3, Claudio Espinoza4, Raúl Vivar5, David Silva2, José Miguel Osorio4, Sergio Lavandero6, Concepción Peiró7, Carlos Sánchez-Ferrer7, Guillermo Díaz-Araya8. 1. Department of Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. 2. Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. 3. Department of Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), Spain. 4. Department of Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile. 5. Pharmacology Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago, Chile. 6. Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile; Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. 7. Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Hospital Universitario La Paz (IdiPAZ), Spain. 8. Department of Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile. Electronic address: gadiaz@ciq.uchile.cl.
Abstract
AIMS: Despite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II. METHODS AND RESULTS: Alzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 μg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1β, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension. CONCLUSIONS: This study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.
AIMS: Despite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II. METHODS AND RESULTS: Alzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 μg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1β, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension. CONCLUSIONS: This study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.
Authors: Menglong Wang; Jishou Zhang; Mengmeng Zhao; Jianfang Liu; Jing Ye; Yao Xu; Zhen Wang; Di Ye; Dan Li; Jun Wan Journal: Front Pharmacol Date: 2022-01-05 Impact factor: 5.810