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Studies have demonstrated that angiotensin II has been involved in immune and inflammatory responses which might contribute to the pathogenesis of immune-mediated diseases. Recent evidence suggests that oxidative stress may play a role in myocarditis. Here, we investigated whether olmesartan, an AT1R antagonist protects against experimental autoimmune myocarditis (EAM) by suppression of oxidative stress, endoplasmic reticulum (ER) stress and inflammatory cytokines. EAM was induced in Lewis rats by immunization with porcine cardiac myosin, were divided into two groups and treated with either olmesartan (10 mg/kg/day) or vehicle for a period of 21 days. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Treatment with olmesartan attenuated the myocardial mRNA expressions of proinflammatory cytokines, [Interleukin (IL)-1β, monocyte chemoattractant protein-1, tumor necrosis factor-α and interferon-γ)] and the protein expression of tumor necrosis factor-α compared with that of vehicle-treated rats. Myocardial protein expressions of AT1R, NADPH oxidase subunits (p47phox, p67phox, gp91phox) and the expression of markers of oxidative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), and the cardiac apoptosis were also significantly decreased by the treatment with olmesartan compared with those of vehicle-treated rats. Furthermore, olmesartan treatment down-regulated the myocardial expressions of glucose regulated protein-78, growth arrest and DNA damage-inducible gene, caspase-12, phospho-p38 mitogen-activated protein kinase (MAPK) and phospho-JNK. These findings suggest that olmesartan protects against EAM in rats, at least in part via suppression of oxidative stress, ER stress and inflammatory cytokines.

Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.

Edaravone, a novel antioxidant, acts by trapping hydroxyl radicals, quenching active oxygen and so on. Its cardioprotective activity against experimental autoimmune myocarditis ( EAM) was reported. Nevertheless, it remains to be determined whether edaravone protects against cardiac remodelling in dilated cardiomyopathy ( DCM). The present study was undertaken to assess whether edaravone attenuates myocardial fibrosis, and examine the effect of edaravone on cardiac function in rats with DCM after EAM. Rat model of EAM was prepared by injection with porcine cardiac myosin 28 days after immunization, we administered edaravone intraperitoneally at 3 and 10 mg/kg/day to rats for 28 days. The results were compared with vehicle-treated rats with DCM. Cardiac function, by haemodynamic and echocardiographic study and histopathology were performed. Left ventricular ( LV) expression of NADPH oxidase subunits (p47phox, p67phox, gp91phox and Nox4), fibrosis markers ( TGF-β1 and OPN), endoplasmic reticulum ( ER) stress markers ( GRP78 and GADD 153) and apoptosis markers (cytochrome C and caspase-3) were measured by Western blotting. Edaravone-treated DCM rats showed better cardiac function compared with those of the vehicle-treated rats. In addition, LV expressions of NADPH oxidase subunits levels were significantly down-regulated in edaravone-treated rats. Furthermore, the number of collagen-III positive cells in the myocardium of edaravone-treated rats was lower compared with those of the vehicle-treated rats. Our results suggest that edaravone ameliorated the progression of DCM by modulating oxidative and ER stress-mediated myocardial apoptosis and fibrosis. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme-2 (ACE-2) is a monocarboxypeptidase that metabolises angiotensin (ANG)-II into angiotensin 1-7 (ANG 1-7), thereby functioning as a negative regulator of the renin-angiotensin system. We investigated whether treatment with ANG-II type 1 receptor blocker, olmesartan medoxomil is associated with the attenuation of cardiac myosin-induced dilated cardiomyopathy (DCM) through recently established new axis of ACE-2/ANG 1-7 mas receptor. DCM was elicited in Lewis rats by immunisation with cardiac myosin, and 28 days after immunisation, the surviving Lewis rats were divided into two groups and treated with either olmesartan medoxomil (10 mg/kg/day) or vehicle. Myocardial protein and mRNA levels of ACE-2, ANG 1-7 mas receptor were upregulated in the olmesartan-treated group compared with those of vehicle-treated DCM rats. In contrast, Olmesartan treatment effectively suppressed the myocardial protein and mRNA expressions of inflammatory markers in comparison to the vehicle-treated DCM rats. Olmesartan treatment significantly reduced fibrosis, hypertrophy and their marker molecules (OPN, CTGF, ANP and GATA-4, respectively), as well as matrix metalloproteinases compared with those of vehicle-treated DCM rats. Enhanced myocardial protein levels of phospho-p38 MAPK, phospho-JNK and phospho MAPKAPK-2 in the vehicle-treated DCM rats were prevented by olmesartan treatment. In addition, olmesartan treatment significantly lowered the protein expressions (Nitrotyrosine, p47phox and p67phox) and superoxide radical production compared with those of vehicle-treated DCM rats. Our present study might serve as a new therapeutic target of DCM in cardiovascular diseases and cardiac myosin-induced DCM via the modulation of ACE-2/ANG 1-7 mas receptor axis in rats with DCM after myosin-immunisation. [ABSTRACT FROM AUTHOR]

The aim was to evaluate the role of the combination of olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), with daunorubicin (DNR) in reducing cardiac toxicity in rats. DNR was administered at a dose of 3 mg/kg/day every other day for 12 days. Olmesartan was administered orally every day for 12 days. Rats treated with DNR alone showed cardiac toxicity as evidenced by worsening cardiac function, elevation of malondialdehyde level in heart tissue and decreased in the level of total glutathione peroxidase activity; treatment with ARB reversed these changes. Furthermore, ARB treatment down-regulated matrix metalloproteinase-2 expression, myocardial expression of Ang II, attenuated the increased protein expressions of p67phox and Nox4 and reduced oxidative stress-induced DNA damage evaluated by expression of 8-hydroxydeoxyguanosine. In conclusion, the result demonstrated that Ang II and oxidative stress play a key role in anthracycline-induced cardiotoxicity and that treatment with ARB will be beneficial against DNR-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Experimental autoimmune myocarditis (EAM) is mediated by myocardial infiltration by myosin-specific T-cells secreting inflammatory cytokines. In this study, rat models of EAM were prepared by injection with porcine cardiac myosin. One week after immunization, edaravone was administered intraperitoneally at 3 or 10 mg/kg/day to rats for 2 weeks. Cardiac function was measured by haemodynamic and echocardiographic studies and TUNEL assay was performed. Left ventricular (LV) expression of NADPH oxidase sub-units (p47phox and p67phox), pro-inflammatory cytokines (TNF-α), endoplasmic reticulum (ER) stress signalling proteins (GRP78, caspase-12 and GADD153) and mitogen-activated protein kinase (MAPK) family proteins (phospho-p38 MAPK and phospho-JNK) were measured by western blotting. Edaravone improved LV function in a dose-dependent manner. Central venous pressure was significantly low and LV ejection fraction and fractional shortening was significantly high in edaravone groups compared with those in the vehicle group. In addition, edaravone treatment down-regulated LV expressions of p47phox, TNF-α, GADD153, phospho-p38 MAPK and phospho-JNK. Furthermore, the LV expressions of p67phox, GRP78, caspase-12 and TUNEL-positive cells of rats with EAM treated with edaravone were significantly low compared with those of the vehicle group. These findings suggest that edaravone ameliorated the progression of EAM by inhibiting oxidative and ER stress and, subsequently, cardiac apoptosis. [ABSTRACT FROM AUTHOR]

The p38 mitogenactivated protein kinase (MAPK) is activated during heart diseases that might be associated with myocardial damage and cardiac remodeling process. Diabetic cardiomyopathy is associated with in creased oxidative stress and inflammation. The purpose of this study was to investigate the role of p38α MAPK after experimental diabetes by using transgenic (TG) mice with cardiacspecific expression of a dominantnegative mutant form of p38α MAPK. The elevation of blood glucose was comparable between the nontransgenic (NTG) and TG mice. The expression of phosphop38 MAPK and phospho MAPKactivated protein kinase 2 levels were significantly suppressed in TG mice heart than in NTG mice after diabetes induction. Left ventricular (LV) dimension in systole was smaller, and the percent fractional shortening was higher in diabetic TG mice compared with diabetic NTG mice. In addition, diabetic TG mice had reduced cardiac myocyte diameter, content of cardiac fibrosis, LV tissue expressions of atrial natriuretic peptide, transforming growth factor β 1, and collagen III compared with diabetic NTG mice. Moreover, LV ex pression of NADPH oxidase subunits, p22phox, p67phox, gp9 1phox, and Nox4, reactive oxygen species and lipid peroxidation levels were significantly increased in diabetic NTG mice, but not in diabetic TO mice. Furthermore, myocardial apoptosis, the number of caspase-3-positive cells, and the downregulation of antiapoptotic protein Bcl-XL were less in diabetic TG mice compared with diabetic NTO mice. In conclusion, our data establish that p38α MAPK activity is required for cardiac remodeling after diabetes induction and suggest that p38α MAPK may promote cardiomyocyte apoptosis by downregulation of Bcl-XL. [ABSTRACT FROM AUTHOR]

It is generally believed that a mechanical signal initiates a cascade of biological events leading to coordinated cardiac remodeling. 14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. To evaluate the molecular mechanism underlying swimming stress-induced cardiac remodeling, we examined the role of 14-3-3 protein and MAPK pathway by pharmacological and genetic means using transgenic mice with cardiac-specific expression of dominant-negative (DN) mutants of 14-3-3 (DN 14-3-3/TG) and p38α/β MAPK (DNp38α and DNp38β) mice. p38 MAPK activation was earlier, more marked, and longer in the myocardium of the TG group compared with that of the nontransgenic (NTG) group after swimming stress, whereas JNK activation was detected on clay 5 and decreased afterward. In contrast, ERK1/2 was not activated after swimming stress in either group. Cardiomyocyte apoptosis, cardiac hypertrophy, and fibrosis were greatly increased in the TG group compared with those in the NTG group. Moreover, we found a significant correlation between p38 MAPK activation and apoptosis in the TG group. Furthermore, DN 14-3-3 hearts showed enhanced atrial natriuretic peptide expression. In contrast, DNp38α and DNp38β mice exhibited reduced mortality and increased resistance to cardiac remodeling after 28 days of swimming stress compared with TG and NTG mice. Besides, treatment with a p38 MAPK inhibitor, FR-167653, resulted in regression of cardiac hypertrophy and fibrosis and improvement in the survival rate in the TG group. These results indicate for the first time that 14-3-3 protein along with p38 MAPK plays a crucial role in left ventricular remodeling associated with swimming stress. [ABSTRACT FROM AUTHOR]

Exocrinopathy and pancreatitis-like injury were developed in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus, which is known to induce murine acquired immunodeficiency syndrome (MAIDS). The role of chemokines, especially CXCL10/interferon (IFN)-γ-inducible protein 10 (IP-10), a chemokine to attract CXCR3+ T helper 1-type CD4+ T cells, has not been investigated thoroughly in the pathogenesis of pancreatitis. B6 mice were inoculated intraperitoneally with LP-BM5 and then injected every week with either an antibody against IP-10 or a control antibody. Eight weeks after infection, we analyzed the effect of IP-10 neutralization. Anti-IP-10 antibody treatment did not change the generalized lymphadenopathy and hepatosplenomegaly of mice with MAIDS. The treatment significantly reduced the number of IP-10- and CXCR3-positive cells in the mesenteric lymph nodes (mLNs) but not the phenotypes and gross numbers of cells. In contrast, IP-10 neutralization reduced the number of mononuclear cells infiltrating into the pancreas. Anti-IP-10 antibody treatment did not change the numbers of IFN-γ+ and IL10+ cells in the mLN but significantly reduced their numbers, especially IFN-γ+ and IL-10+ CD4+ T cells and IFN-γ+ Mac-1+ cells, in the pancreas. IP-10 neutralization ameliorated the pancreatic lesions of mice with MAIDS probably by blocking the cellular infiltration of CD4+ T cells and IFN-γ+ Mac-1+ cells into the pancreas at least at 8 wk after infection, suggesting that IP-10 and these cells might play a key role in the development of chronic autoimmune pancreatitis. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and ±dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-α, and improved sarcoplasmic reticulum Ca2+ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]