ABSTRACT
FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Subject(s)
Animals , Male , Rats , Benzamides/pharmacology , Endomyocardial Fibrosis/drug therapy , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Blotting, Western , Benzamides/therapeutic use , Blood Pressure/drug effects , Desoxycorticosterone , Disease Models, Animal , Endomyocardial Fibrosis/pathology , Fibronectins/analysis , Fibronectins/metabolism , Fibrosis/drug therapy , Fibrosis/pathology , Hypertension/chemically induced , Hypertension/physiopathology , Nephrectomy/methods , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Rats, Sprague-Dawley , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism , Treatment Outcome , Tenascin/analysis , Tenascin/metabolismABSTRACT
BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRß) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were significantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.
Subject(s)
Benzamides/pharmacology , Endomyocardial Fibrosis/drug therapy , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Animals , Benzamides/therapeutic use , Blood Pressure/drug effects , Blotting, Western , Desoxycorticosterone , Disease Models, Animal , Endomyocardial Fibrosis/pathology , Fibronectins/analysis , Fibronectins/metabolism , Fibrosis/drug therapy , Fibrosis/pathology , Hypertension/chemically induced , Hypertension/physiopathology , Imatinib Mesylate , Male , Nephrectomy/methods , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism , Tenascin/analysis , Tenascin/metabolism , Treatment OutcomeABSTRACT
Gaseous Fe(4)S(n)(-) (n = 4-6) clusters and synthetic analogue complexes, Fe(4)S(4)L(n)(-) (L = Cl, Br, I; n = 1-4), were produced by laser vaporization of a solid Fe/S target and electrospray from solution samples, respectively, and their electronic structures were probed by photoelectron spectroscopy. Low binding energy features derived from minority-spin Fe 3d electrons were clearly distinguished from S-derived bands. We showed that the electronic structure of the simplest Fe(4)S(4)(-) cubane cluster can be described by the two-layer spin-coupling model previously developed for the [4Fe] cubane analogues. The photoelectron data revealed that each extra S atom in Fe(4)S(5)(-) and Fe(4)S(6)(-) removes two minority-spin Fe 3d electrons from the [4Fe--4S] cubane core and each halogen ligand removes one Fe 3d electron from the cubane core in the Fe(4)S(4)L(n)(-) complexes, clearly revealing a behavior of sequential oxidation of the cubane over five formal oxidation states: [4Fe--4S](-) --> [4Fe--4S](0) --> [4Fe--4S](+) --> [4Fe-4S](2+) --> [4Fe-4S](3+). The current work shows the electron-storage capability of the [4Fe--4S] cubane, contributes to the understanding of its electronic structure, and further demonstrates the robustness of the cubane as a structural unit and electron-transfer center.