RESUMO
The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT1 receptor (AT1R). Ang-(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by ß-arrestin-biased agonists has been associated to cardioprotection. Because position 8 in AngII is important for G protein activation, we hypothesized that Ang-(1-7) could be an endogenous ß-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering ß-arrestins 1 and 2 recruitment and activation. Using an in vivo model of cardiac hypertrophy, we show that Ang-(1-7) significantly attenuates heart hypertrophy by reducing both heart weight and ventricular wall thickness and the increased end-diastolic pressure. Whereas neither the single blockade of AT1 or Mas receptors with their respective antagonists prevented the cardioprotective action of Ang1-7, combination of the two antagonists partially impaired the effect of Ang-(1-7). Taken together, these data indicate that Ang-(1-7) mediates at least part of its cardioprotective effects by acting as an endogenous ß-arrestin-biased agonist at the AT1R.
Assuntos
Angiotensina I/uso terapêutico , Cardiomegalia/tratamento farmacológico , Cardiotônicos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Receptor Tipo 1 de Angiotensina/metabolismo , beta-Arrestinas/agonistas , Angiotensina I/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Cardiotônicos/metabolismo , Diástole/efeitos dos fármacos , Células HEK293 , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosforilação , Ratos , Ratos Endogâmicos WF , Transdução de Sinais/efeitos dos fármacos , beta-Arrestinas/metabolismoRESUMO
HIV patients are predisposed to the development of hypertriglyceridemia and hypercholesterolemia as a result of both viral infection and HIV infection therapy, especially the protease inhibitors. Chemokines and cytokines are present at sites of inflammation and can influence the nature of the inflammatory response in atherosclerosis. We investigated the correlation between biochemical variables and beta-chemokines (MIP-1alpha and RANTES) and the apolipoprotein E genotype in HIV-infected individuals. The apolipoproteins were measured by nephelometry. Triglycerides and total cholesterol were determined by standard enzymatic procedures. The beta-chemokines were detected by ELISA. The genetic category of CCR5 and apolipoprotein E were determined by PCR amplification and restriction enzymes. Immunological and virological profiles were assessed by TCD(4)+ and TCD(8)+ lymphocyte counts and viral load quantification. Positive correlations were found between apo E and CD(8)+ (p = 0.035), apo E and viral load (p = 0.018), MIP-1alpha and triglycerides (p = 0.039) and MIP-1a and VLDL (p = 0.040). Negative correlations were found between viral load and CD(4)+ (p = 0.05) and RANTES and CD(4)+ (p = 0.029). The beta-chemokine levels may influence lipid metabolism in HIV-infected individuals.
Assuntos
Apolipoproteínas E/sangue , Quimiocina CCL5/sangue , Infecções por HIV/sangue , Lipoproteínas/sangue , Proteínas Inflamatórias de Macrófagos/sangue , Adulto , Apolipoproteínas E/genética , Biomarcadores/sangue , Relação CD4-CD8 , Quimiocina CCL3 , Quimiocina CCL4 , Feminino , Genótipo , Humanos , Masculino , Receptores CCR5/sangue , Carga ViralRESUMO
HIV patients are predisposed to the development of hypertriglyceridemia and hypercholesterolemia as a result of both viral infection and HIV infection therapy, especially the protease inhibitors. Chemokines and cytokines are present at sites of inflammation and can influence the nature of the inflammatory response in atherosclerosis. We investigated the correlation between biochemical variables and beta-chemokines (MIP-1alpha and RANTES) and the apolipoprotein E genotype in HIV-infected individuals. The apolipoproteins were measured by nephelometry. Triglycerides and total cholesterol were determined by standard enzymatic procedures. The beta-chemokines were detected by ELISA. The genetic category of CCR5 and apolipoprotein E were determined by PCR amplification and restriction enzymes. Immunological and virological profiles were assessed by TCD4+ and TCD8+ lymphocyte counts and viral load quantification. Positive correlations were found between apo E and CD8+ (p = 0.035), apo E and viral load (p = 0.018), MIP-1alpha and triglycerides (p = 0.039) and MIP-1a and VLDL (p = 0.040). Negative correlations were found between viral load and CD4+ (p = 0.05) and RANTES and CD4+ (p = 0.029). The beta-chemokine levels may influence lipid metabolism in HIV-infected individuals.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Apolipoproteínas E/sangue , Quimiocina CCL5 , Infecções por HIV/sangue , Lipoproteínas/sangue , Proteínas Inflamatórias de Macrófagos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Biomarcadores/sangue , Quimiocina CCL5 , Ensaio de Imunoadsorção Enzimática , Genótipo , Infecções por HIV/metabolismo , Lipoproteínas/metabolismo , Proteínas Inflamatórias de Macrófagos , Nefelometria e Turbidimetria , Reação em Cadeia da Polimerase , /sangue , Carga ViralRESUMO
HIV infection is associated with disturbances in lipid metabolism due to a host's response mechanism and the current antiretroviral therapy. The pathological appearance and progression of atherosclerosis is dependent on the presence of injurious agents in the vascular endothelium and variations in different subsets of candidate genes. Therefore, the Hha I polymorphism in the apolipoprotein E gene was evaluated in addition to triglycerides, total cholesterol, very low-density lipoprotein (VLDL), LDL, high-density lipoprotein (HDL), and apolipoprotein (apo) Al, B and E levels in 86 Brazilian HIV-infected patients and 29 healthy controls. The allele frequency for apoE in the HIV-infected group and controls was in agreement with data on the Brazilian population. Dyslipidemia was observed in the HIV group and verified by increased levels of triglycerides, VLDL and apoE, and decreased levels of HDL and apoAl. The greatest abnormalities in these biochemical variables were shown in the HIV-infected individuals whose immune function was more compromised. The effect of the genetic variation at the APOE gene on biochemical variables was more pronounced in the HIV-infected individuals who carried the apoE2/3 genotype. The highly active anti-retroviral therapy (HAART)-receiving group presented increased levels of total cholesterol and apoE. Dyslipidemia was a predictable consequence of HIV infection and the protease inhibitors intensified the increase in apoE values.