RESUMO
Triptolide is the predominant active component of the Chinese herb Tripterygium wilfordii Hook F (TwHF) that has been widely used to treat several chronic inflammatory diseases due to its immunosuppressive, anti-inflammatory, and anti-proliferative properties. In the present study, we elucidated the cardioprotective effects of triptolide against cardiac dysfunction and myocardial remodeling in chronic pressure-overloaded hearts. Furthermore, the potential mechanisms of triptolide were investigated. For this purpose, C57/BL6 mice were anesthetized and subjected to transverse aortic constriction (TAC) or sham operation. Six weeks after the operation, all mice were randomly divided into 4 groups: sham-operated with vehicle group, TAC with vehicle group, and TAC with triptolide (20 or 100 µg/kg/day intraperitoneal injection) groups. Our data showed that the levels of NLRP3 inflammasome were significantly increased in the TAC group and were associated with increased inflammatory mediators and profibrotic factor production, resulting in myocardial fibrosis, cardiomyocyte hypertrophy, and impaired cardiac function. Triptolide treatment attenuated TAC-induced myocardial remodeling, improved cardiac diastolic and systolic function, inhibited the NLRP3 inflammasome and downstream inflammatory mediators (IL-1ß, IL-18, MCP-1, VCAM-1), activated the profibrotic TGF-ß1 pathway, and suppressed macrophage infiltration in a dose-dependent manner. Our study demonstrated that the protective effect of triptolide against pressure overload in the heart may act by inhibiting the NLRP3 inflammasome-induced inflammatory response and activating the profibrotic pathway.
Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenantrenos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Diterpenos/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Compostos de Epóxi/química , Compostos de Epóxi/uso terapêutico , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/imunologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/imunologia , Hipertrofia Ventricular Esquerda/patologia , Imunidade Inata/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fenantrenos/química , Tripterygium/químicaRESUMO
OBJECTIVE: To investigate the effects of sapindus saponins on myocardial inflammation mediated by Ang II/ p38MAPK signal pathway and cardiac hypertrophy in spontaneously hypertensive rats. And also to explore the correlation of cardiac hypertrophy and inflammation. METHOD: Thirty-two 16-week-old spontaneously hypertensive rats (SHR) were randomly divided into four groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators detected were as follows: (1) left ventricular mass index (LVMI); (2) the content of Ang II and hs-CRP in plasma were determined by ELISA; (3) the protein expression of AT1R and VEGF were determined by immunohistochemical method; (4) the protein expression of p-p38MAPK in myocardial cells was determined by Western blot. RESULT: Sapindus saponins reduced LVMI, and blocked the expression level of Ang II, AT1R, p-p38MAPK, VEGF and hs-CRP in myocardial tissue. Vs the SHR model group, there were significant differences (P < 0.05 or P < 0.01). CONCLUSION: Our findings suggested that sapindus saponins could inhibited cardiac hypertrophy, the possible mechanisms may be related to the inhibition on inflammatory response mediated by Ang II/p38MAPK pathway.
Assuntos
Angiotensina II/imunologia , Medicamentos de Ervas Chinesas/administração & dosagem , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Sapindus/química , Saponinas/administração & dosagem , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/complicações , Hipertensão/imunologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/imunologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos WistarRESUMO
BACKGROUND: Aortic stiffness and left ventricular hypertrophy (LVH) are predictors of mortality in hemodialysis (HD) patients. Attenuation of arterial stiffness and regression of LVH had a favorable effect on survival in these patients, but this favorable effect was observed in less than 50% of patients, the rest being resistant to therapeutical interventions. The aim of this study was to analyze the factors associated with this resistance to treatment. METHODS: 138 patients on HD were studied during a follow-up survey. From entry until the end of follow up, the changes of aortic pulse wave velocity (PWV) and of LV mass were measured in response to treatment with antihypertensive drugs and erythropoietin, together with measurements of blood chemistry, including high-sensitive C-reactive protein (CRP). Patients with decreased aortic PWV were considered to be responders (N = 68), the others to be nonresponders (N = 70). RESULTS: Nonresponders were older (P < 0.05) and had persistently higher systolic blood pressure (BP) and pulse pressure. Responders were treated more frequently with an ACE inhibitor (P < 0.001), and had lower serum CRP (P < 0.01). The baseline PWV, as well as the changes of PWV and LV mass during the follow-up were significantly and independently correlated with serum CRP level (P < 0.001). According to logistic regression after adjustment for age, gender, diabetes, history of CVD, and the nonspecific cardiovascular risk factors, the improvement of aortic stiffness and LV hypertrophy was positively associated with prescription of ACE inhibitor (P < 0.0001), and negatively with the serum CRP level (P < 0.01). CONCLUSION: These results indicate that in HD patients, the presence of low-grade inflammation decreases the efficiency of cardiovascular therapeutic interventions and participates in the persistence of cardiovascular hemodynamic overload.