RESUMO
The incidence of chronic kidney disease is escalating; cardiorenal syndrome (CRS) type 4 is gaining a major health concern causing significant morbidity and mortality, putting major burdens on the healthcare system. This study was designed to compare the cardioprotective effects of carvedilol versus atenolol against CRS type 4 induced by subtotal 5/6 nephrectomy in rats and to explore the underlying mechanisms. Immediately after surgery, carvedilol (20 mg/kg/day) or atenolol (20 mg/kg/day) was added to drinking water for 10 weeks. Carvedilol was more effective than atenolol in improving kidney functions, decreasing elevated blood pressures, attenuating cardiac hypertrophy, reducing serum brain natriuretic peptide, and diminished cardiac fibrous tissue deposition. However, carvedilol was equivalent to atenolol in modulating ß1-adrenergic receptors (ß1ARs) and cardiac diacylglycerol (DAG) signaling, but carvedilol was superior in modulating ß-arrestin2, phosphatidyl inositol 4,5 bisphosphates (PIP2), and caspase 3 levels. Carvedilol has superior cardioprotective effects than atenolol in a rat model of CRS type 4. These protective effects are mediated through modulating cardiac ß1ARs/ß-arrestin2/PIP2/DAG as well as abating cardiac apoptotic signaling pathways (caspase3/pS473 protein kinase B (Akt)).
Assuntos
Atenolol/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Cardiomegalia/tratamento farmacológico , Cardiotônicos/uso terapêutico , Carvedilol/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/fisiopatologia , Síndrome Cardiorrenal/cirurgia , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Cardiomegalia/cirurgia , Cardiotônicos/farmacologia , Carvedilol/farmacologia , Diacilglicerol Quinase/metabolismo , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Miocárdio/metabolismo , Nefrectomia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Ratos Wistar , Receptores Adrenérgicos beta 1/metabolismo , beta-Arrestina 2/metabolismoRESUMO
Glycogen synthase kinase-3ß (GSK-3ß) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3ß in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3ß (GSK-3ß(+/-) KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3ß(+/-) KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3ß(+/-) KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac ß-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3ß(+/-) KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3ß is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.