BACKGROUNDTransforming growth factor (TGF) beta(1)-Smads signal plays an important role in cardiac remodeling following myocardial infarction (MI). In addition, both angiotensin converting enzyme inhibitor (ACEI) and angiotensin II type I receptor blocker (ARB) can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect.

METHODSMI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks: placebo group, ACEI group (benazepril 10 mg.kg(-1).d(-1)), ARB group (irbesartan 50 mg.kg(-1).d(-1)), ACEI + ARB group (benazepril 10 mg.kg(-1).d(-1) + irbesartan 50 mg.kg(-1).d(-1)) and control group (sham-operated rats). After 8 weeks, we examined the following indexes: the ratio of ventricular weight to body weight (VW/BW), left ventricular end diastolic dimension (LVDd), ejection fraction (EF), fractional shortening (FS), ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFbeta(1), Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot.

RESULTSVW/BW significantly increased in the placebo groups compared with that in the control group (P < 0.01). This increase was limited in ACEI, ARB, and combined groups (P < 0.01 compared with placebo group). There was no significant difference among the three actively treated groups. Collagen was increased in placebo group (5.68 +/- 0.5)% compared with that in control group (P < 0.01). ACEI, ARB and combined treatment attenuated this increase of collagen [(4.3 +/- 0.5)%, (3.5 +/- 0.5)%, (3.2 +/- 0.4)%] in comparison with that in placebo group (P < 0.01 respectively). Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group (P < 0.01 respectively). ACEI, ARB and combined treatment ameliorated these indexes (P < 0.01 compared with placebo group). The mRNA expression of TGFbeta(1), Smad 2, and Smad 3 (0.700 +/- 0.045, 0.959 +/- 0.037 and 0.850 +/- 0.051) increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF beta(1) and Smad mRNA expression than ACEI treatment (P < 0.01). The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group (P < 0.01). ACEI, ARB and combined treatment normalized the increase (P < 0.01). Furthermore, ARB and combined treatment proved to be more effective than ACEI alone (P < 0.01).

CONCLUSIONSTGFbeta(1)-Smads signal activation is correlated with ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.

Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; administration & dosage ; therapeutic use ; Animals ; Drug Therapy, Combination ; Echocardiography ; Male ; Myocardial Infarction ; drug therapy ; Rats ; Rats, Wistar ; Smad2 Protein ; analysis ; genetics ; Smad3 Protein ; analysis ; genetics ; Transforming Growth Factor beta ; genetics ; Transforming Growth Factor beta1 ; Ventricular Remodeling ; drug effects

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.
Humans ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Cisplatin/metabolism* ; Esophageal Neoplasms/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Carcinoma, Squamous Cell/genetics* ; Growth Differentiation Factor 15/therapeutic use* ; Receptor, Transforming Growth Factor-beta Type II/therapeutic use* ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic

BACKGROUNDS AND AIMS: Angiotensin receptors are found on hepatic stellate cells, which participate in hepatic fibrosis. Therefore, it is presumed that angiotensin has a role in hepatic fibrosis. The aim of this study was to evaluate the effects of angiotensin blockade on inhibition of hepatic fibrosis in cirrhotic rat model. Material and METHODS: Cirrhosis with portal hypertension was produced by common bile duct ligation (BDL) in the adult Sprague-Dawley rats. They were classified into 4 groups (each group n=6) as follows; G1: BDL without drug, G2: BDL+captopril 100 mg/kg/day beginning 2 weeks after BDL, G3: BDL+captopril 100 mg/kg/day, starting just after BDL, G4: BDL+losartan 10 mg/kg/day, starting just after BDL. After 4 weeks following BDL, hepatic fibrosis was histomorphologically analyzed by Batts & Ludwig score. Alpha smooth muscle actin by immunohistochemical stain, hydroxyproline contents of liver tissue by spectrophotometry and expression of collagen, procollagen, and TGF-beta by real-time PCR were measured. RESULTS: Batts & Ludwig score were 3.8, 3.0, 2.6,and 2.6 in G1, G2, G3, and G4, respectively. The expression of alpha-SMA was significantly lower in G3 and G4 than in G1; 11.9%, 10.9%, 2.6%, and 1.1% in G1, G2, G3, and G4, respectively (p<0.05). The concentration of hydroxyproline (microgram/g liver tissue) was lower in G3 and G4 compared with G1 (p<0.05). Also, the administration of angiotensin blockade just after BDL significantly reduced the expression of collagen, procollagen, and TGF-beta mRNA. CONCLUSIONS: Angiotensin blockades are effective in the prevention of hepatic fibrosis in BDL rats.
Actins/metabolism ; Angiotensin II Type 1 Receptor Blockers/administration & dosage/*therapeutic use ; Animals ; Bile Ducts/pathology/surgery ; Captopril/administration & dosage/*therapeutic use ; Fibrosis ; Hydroxyproline/metabolism ; Ligation ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis, Experimental/*drug therapy/etiology/metabolism ; Losartan/administration & dosage/*therapeutic use ; Male ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta/metabolism

OBJECTIVEChildren with nephrotic syndrome are always associated with retardation of growth. Growth hormone (GH) administration to these children can stimulate their growth, but it plays an important role in glomerulosclerosis. Thus these children would take a risk to use it to improve their growth. This study was designed to investigate the effect of GH on the kidney of rats with adriamycin-induced nephropathy (AN) and its mechanism, and to observe the renoprotective effect of angiotensin II (AngII) receptor antagonist, irbesartan, in GH-treated AN rats.

METHODSRats were divided into the following groups: normal control rats, AN rats, GH-treated AN rats and GH plus irbesartan-treated AN rats. There were 8 developing male SD rats (120-130 g) in each group. Urinary protein was measured at weeks 3, 6 and 9. Blood pressure, serum creatinine, BUN, albumin, cholesterol, triglyceride, as well as ACE activity and AngII concentration of the kidney were detected at the end of the study. Renal pathological changes were evaluated also. Immunohistochemistry was used to examine the protein expressions of TGF beta(1), collagen IV and fibronectin in glomeruli.

RESULTSGlomerular sclerosis score of GH-treated AN rats (49.4 +/- 9.8) was significantly higher than that of AN rats (12.8 +/- 5.5, P < 0.01), and this score of GH-treated AN rats plus irbesartan (26.2 +/- 7.5) was significantly lower than the score of GH-treated AN rats (P < 0.01). The changes of urinary protein, hyperlipidemia and hypoalbuminemia in rats of each group consisted with the degree of glomerular injury in rats of each group. There was azotemia in GH-treated AN rats, but rats in the other groups did not have azotemia. ACE activity of kidney was significantly (P < 0.01) increased in GH-treated AN rats [(28.1 +/- 4.1) U/mg pro] and GH-treated AN rats plus irbesartan [(27.6 +/- 3.4) U/mg pro] compared with that in AN rats [(14.6 +/- 4.4) U/mg pro]. AngII concentrations in the kidney of GH-treated AN rats [(17.8 +/- 3.3) pg/mg pro] and GH-treated AN rats plus irbesartan [(27.3 +/- 5.1) pg/mg pro] were significantly higher than that in AN rats [(8.3 +/- 1.9) pg/mg pro] (P < 0.01). The protein expressions of TGF-beta(1), collagen IV and fibronectin in GH-treated AN rats were the most distinct in all groups. These expressions were significantly (P < 0.05) reduced in GH-treated AN rats plus irbesartan.

CONCLUSIONGH is able to exacerbate adriamycin-induced nephropathy in rats, which was partly through activating renal tissue RAS and initiating the function of the AngII-TGF beta(1)-ECM axis. Angiotensin II receptor antagonist, irbesartan, has some renal protective effects on AN rats treated with GH.

Angiotensin II ; analysis ; Angiotensin Receptor Antagonists ; Animals ; Antibiotics, Antineoplastic ; toxicity ; Biphenyl Compounds ; pharmacology ; therapeutic use ; Blood Urea Nitrogen ; Collagen Type IV ; analysis ; Creatinine ; blood ; Disease Models, Animal ; Doxorubicin ; toxicity ; Fibronectins ; analysis ; Growth Hormone ; pharmacology ; Immunohistochemistry ; Kidney Diseases ; chemically induced ; drug therapy ; Kidney Glomerulus ; chemistry ; drug effects ; pathology ; Male ; Peptidyl-Dipeptidase A ; analysis ; Proteinuria ; urine ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Serum Albumin ; metabolism ; Tetrazoles ; pharmacology ; therapeutic use ; Transforming Growth Factor beta ; analysis ; Triglycerides ; blood