Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress.

BACKGROUND AND PURPOSE: ST2 is one of the interleukin (IL)-1 receptor family members comprising of membrane-bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non-ischemic HF. Here, we tested whether IL-33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL-33-/-) mice. METHODS AND RESULTS: Transverse aortic constriction (TAC)/sham surgery were carried out in both IL-33 and WT-littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF-α were enhanced in IL-33-/- mice than in WT mice. After 8-weeks, IL-33-/- mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c-Myc/BNP) molecular markers were also significantly enhanced in IL-33-/- mice than those in WT mice. CONCLUSIONS: We report for the first time that ablation of IL-33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL-33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL-33 in non-ischemic HF.

Molecular understanding of curcumin in diabetic nephropathy.

Diabetic nephropathy is characterized by a plethora of signaling abnormalities. Recent trials have suggested that intensive glucose-lowering treatment leads to hypoglycemic events, which can be dangerous. Curcumin is the active ingredient of turmeric, which has been widely used in many countries for centuries to treat numerous diseases. The preventive and therapeutic properties of curcumin are associated with its antioxidant and anti-inflammatory properties. Here, we highlight the renoprotective role of curcumin in diabetes mellitus (DM) with an emphasis on the molecular basis of this effect. We also briefly discuss the numerous approaches that have been undertaken to improve the pharmacokinetics of curcumin.

Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis.

Lymphocyte extravasation from the high endothelial venules (HEVs) of lymph nodes is crucial for the maintenance of immune homeostasis, but its molecular mechanism remains largely unknown. In this article, we report that lymphocyte transmigration across the basal lamina of the HEVs is regulated, at least in part, by autotaxin (ATX) and its end-product, lysophosphatidic acid (LPA). ATX is an HEV-associated ectoenzyme that produces LPA from lysophosphatidylcholine (LPC), which is abundant in the systemic circulation. In agreement with selective expression of ATX in HEVs, LPA was constitutively and specifically detected on HEVs. In vivo, inhibition of ATX impaired the lymphocyte extravasation from HEVs, inducing lymphocyte accumulation within the endothelial cells (ECs) and sub-EC compartment; this impairment was abrogated by LPA. In vitro, both LPA and LPC induced a marked increase in the motility of HEV ECs; LPC's effect was abrogated by ATX inhibition, whereas LPA's effect was abrogated by ATX/LPA receptor inhibition. In an in vitro transmigration assay, ATX inhibition impaired the release of lymphocytes that had migrated underneath HEV ECs, and these defects were abrogated by LPA. This effect of LPA was dependent on myosin II activity in the HEV ECs. Collectively, these results strongly suggest that HEV-associated ATX generates LPA locally; LPA, in turn, acts on HEV ECs to increase their motility, promoting dynamic lymphocyte-HEV interactions and subsequent lymphocyte transmigration across the basal lamina of HEVs at steady state.

Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant.

There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPKα, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone.

Olmesartan medoxomil treatment potently improves cardiac myosin-induced dilated cardiomyopathy via the modulation of ACE-2 and ANG 1-7 mas receptor.

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.

Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats.

Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca(2+) ATPase2, p22(phox), receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c-Jun NH(2)-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis.

Beneficial effects of edaravone, a novel antioxidant, in rats with dilated cardiomyopathy.

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 (p47(phox), p67(phox), gp91(phox) and Nox4), fibrosis markers (TGF-ß(1) 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.

Telmisartan acts through the modulation of ACE-2/ANG 1-7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis.

AIM: Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1-7 [ANG 1-7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM]. MAIN METHODS: DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle. KEY FINDINGS: Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1ß, interferon-γ, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE-2 and ANG 1-7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-ß1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen-activated protein kinase (MAPK) signaling molecules than with those of vehicle-treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function. SIGNIFICANCE: These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through the modulation of ACE-2/ANG 1-7/Mas receptor axis in rats with DCM after EAM.

Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor.

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the 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, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.

Depletion of 14-3-3 protein exacerbates cardiac oxidative stress, inflammation and remodeling process via modulation of MAPK/NF-ĸB signaling pathways after streptozotocin-induced diabetes mellitus.

Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. The aim of the study presented here was to clarify the role of 14-3-3 protein in the mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling pathway after experimental diabetes by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3). Significant p-p38 MAPK activation in DN 14-3-3 mice compared to wild type mice (WT) after diabetes induction and with a corresponding up regulation of its downstream effectors, p-MAPK activated protein kinase 2 (MAPKAPK-2). Marked increases in cardiac hypertrophy, fibrosis and inflammation were observed with a corresponding up-regulation of atrial natriuretic peptide, osteopontin, connective tissue growth factor, tumor necrosis factor α, interleukin (IL)-1ß, IL-6 and cellular adhesion molecules. Moreover, reactive oxygen species, left ventricular expression of NADPH oxidase subunits, p22 phox, p67 phox, and Nox4, and lipid peroxidation levels were significantly increased in diabetic DN 14-3-3mice compared to diabetic WT mice. Furthermore, myocardial NF-κB activation, inhibitor of kappa B-α degradation and mRNA expression of proinflammatory cytokines were significantly increased in DN 14-3-3 mice compared to WT mice after diabetes induction. In conclusion, our data suggests that depletion of 14-3-3 protein induces cardiac oxidative stress, inflammation and remodeling after experimental diabetes induction mediated through p38 MAPK, MAPKAPK-2 and NF-κB signaling.

Curcumin attenuates diabetic nephropathy by inhibiting PKC-α and PKC-ß1 activity in streptozotocin-induced type I diabetic rats.

SCOPE: We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-ß1 activity-ERK1/2 pathway. METHODS AND RESULTS: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-ß1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-ß1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin. CONCLUSION: These results prove that curcumin produces dual blockade of both PKC-α and PKC-ß1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Carvedilol-Afforded Protection against Daunorubicin-Induced Cardiomyopathic Rats In Vivo: Effects on Cardiac Fibrosis and Hypertrophy.

Anthracyclines, most powerful anticancer agents, suffer from their cardiotoxic effects, which may be due to the induction of oxidative stress. Carvedilol, a third-generation, nonselective ß-adrenoreceptor antagonist, possesses both reactive oxygen species (ROS) scavenging and ROS suppressive effects. It showed protective effects against daunorubicin- (DNR-) induced cardiac toxicity by reducing oxidative stress and apoptosis. This study therefore was designed to examine the effects of carvedilol on DNR-induced cardiomyopathic rats, focused on the changes of left ventricular function, cardiac fibrosis, and hypertrophy. Carvedilol increased survival rate, prevented systolic and diastolic dysfunction, and attenuated myocardial fibrosis and hypertrophy. DNR alone treated rats showed upregulated myocardial expression of ANP, PKC-α, OPN, and TGF-ß1 and downregulation of GATA-4 in comparison with control, and treatment with carvedilol significantly reversed these changes. The results of the present study add the available evidences on the cardioprotection by carvedilol when associated with anthracyclines and explain the mechanisms underlying the benefits of their coadministration.

Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis.

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.

Curcumin ameliorates cardiac inflammation in rats with autoimmune myocarditis.

Curcumin is a natural polyphenolic compound abundant in the rhizome of the perennial herb turmeric, Curcuma longa. It is commonly used as a dietary spice and coloring agent in cooking, and is used anecdotally as an herb in traditional Indian and Chinese medicine. It has been reported that curcumin has the potential to protect against cardiac inflammation through suppression of GATA-4 and nuclear factor-κB (NF-κB); however, no study to date has addressed the effect of curcumin on experimental autoimmune myocarditis (EAM) in rats. In this study, 8-week-old male Lewis rats were immunized with cardiac myosin to induce EAM. They were then divided randomly into a treatment or vehicle group and orally administrated curcumin (50 mg/kg/d) or 1% gum arabic, respectively, for 3 weeks after myosin injection. We performed hemodynamic, echocardiographic, hematoxylin and eosin staining, mast cell staining and Western blotting studies to evaluate the protective effect of curcumin in the acute phase of EAM. Cardiac functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by curcumin treatment. Furthermore, curcumin reduced the heart weight-to-body weight ratio, area of inflammatory lesions and the myocardial protein level of NF-κB, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and GATA-4. Our results indicate that curcumin has the potential to protect against cardiac inflammation through suppression of IL-1ß, TNF-α, GATA-4 and NF-κB expresses, and may provide a novel therapeutic strategy for autoimmune myocarditis.

Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy.

BACKGROUND: Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced with STZ (55 mg/kg) by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers. RESULTS: At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of IκBα and NF-κB activation and as a result increased infiltration of macrophages (52%) as well as increased proinflammatory cytokines: TNF-α and IL-1ß. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of IκBα. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-ß1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-κB activity. CONCLUSION: Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF-κB activation in STZ-induced diabetic rats.

Regulation of inflammation and myocardial fibrosis in experimental autoimmune myocarditis.

Autoimmune responses and inflammation are involved in the pathogenesis of many cardiovascular diseases. There is compelling evidence that inflammatory mechanisms may contribute to progressive heart failure. Thus, myocardial infiltration of lymphocytes and mononuclear cells, increased expression of pro-inflammatory chemokines and cytokines and circulating autoantibodies are frequently observed in myocarditis and dilated cardiomyopathy (DCM). Experimental autoimmune myocarditis (EAM) in rodents may be elicited by immunization of cardiac myosin and EAM in rats mimics human fulminant myocarditis in the acute phase and human DCM in the chronic phase. Our animal model, EAM was demonstrated to progress into the clinicopathological state similar to DCM in the chronic phase, and was found to be characterized by the enlargement of the heart, dilatation of ventricles, diffuse and extensive myocardial fibrosis, besides being a cellular immunity and inflammation mediated disease. Severity of myocarditis was characterized by increased inflammation, cardiac fibrosis and decreased myocardial performance in rats with DCM. Pharmacological interventions such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) significantly attenuated the myosin-induced inflammation and cardiac fibrosis and thereby improving myocardial function in rats with DCM. A growing body of evidence shows that ACEI and ARBs contribute to the pharmaceutical management of patients with heart failure mediated by immune and inflammatory response. The purpose of this review is to emphasize the role of inflammation and myocardial fibrosis in rats with DCM after EAM and study the effects of pharmacological interventions such as ACEI, ARBs in the treatment of heart failure through the suppression of inflammatory cytokines and fibrosis.

Olmesartan, an AT1 antagonist, attenuates oxidative stress, endoplasmic reticulum stress and cardiac inflammatory mediators in rats with heart failure induced by experimental autoimmune myocarditis.

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 AT(1)R 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)-1ß, 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 AT(1)R, 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.

Telmisartan ameliorates experimental autoimmune myocarditis associated with inhibition of inflammation and oxidative stress.

Excess cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Angiotensin-II has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. Some angiotensin II type 1 receptor antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We investigated whether telmisartan, an angiotensin II type 1 receptor antagonist protects against experimental autoimmune myocarditis by suppression of inflammatory cytokines and oxidative stress. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle for 21days. Age-matched normal rats without immunization were also included in this study. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Increased myocardial mRNA expressions of inflammatory cytokines [interleukin (IL-6), IL-1ß, tumor necrosis factor-α and interferon-γ] were also suppressed by telmisartan treatment compared with vehicle-treated rats. Myocardial protein expressions of NADPH oxidase subunits p47phox, Nox-4, and gp91phox, myocardial levels of 8-hydroxydeoxyguanosine and 4-hydroxy-2-nonenal, and myocardial apoptosis were also significantly decreased by telmisartan treatment compared with vehicle-treated rats. Further, telmisartan significantly decreased endoplasmic reticulum stress markers in experimental autoimmune myocarditis rats. These findings suggest that telmisartan protects against experimental autoimmune myocarditis in rats, at least in part by suppressing inflammatory cytokines and oxidative stress; however, further investigations are needed before clinical use.

Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions.

Angiotensin II (Ang II) receptor blocker (ARB) suppresses the progression of kidney disease. However, there is limited information regarding the nephroprotective effect of ARB in daunorubicin (DNR)-induced nephrotoxicity in rats. We examined the alteration of the renal Ang II and endothelin-1 (ET-1) receptor expression and the action of telmisartan, an ARB, on DNR-induced nephrotoxicity. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Telmisartan was administered orally every day for 6 weeks. DNR rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdehyde level, and the glutathione peroxidase activity in kidney tissue. These changes were reversed by treatment with telmisartan, which resulted in significant improvement in renal function. Furthermore, telmisartan increased nephrin protein expression, and down-regulated renal expression of Ang II and its receptor Ang II type I. Renal protein expressions of ET-1 and its receptor ET-receptor type A were increased in DNR rats, and treatment with telmisartan attenuated these increased expressions. Telmisartan mediated a further increase in the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). In addition, the expressions of cyclooxygenase-2 and cellular adhesion molecules were increased in DNR rats, which were attenuated by telmisartan. In conclusion, telmisartan has a protective effect on DNR-induced nephrotoxicity through Ang II and ET-1, with the alteration of their receptor expressions, which is associated with its anti-inflammatory and anti-oxidant effects at least in part through PPAR-γ agonistic actions.

Effect of telmisartan in limiting the cardiotoxic effect of daunorubicin in rats.

OBJECTIVES: Studies have suggested that angiotensin receptor blockers may exert a protective role towards doxorubicin-induced cardiotoxicity, but they have not been extensively investigated in this area. We therefore investigated whether the co-treatment of telmisartan, an angiotensin (Ang II) type-1 receptor blocker, might offer protection against daunorubicin cardiotoxic properties in rats. METHODS: Daunorubicin was administered at 3 mg/kg/day every other day for 12 days. Telmisartan was administered orally every day for 12 days. KEY FINDINGS: Daunorubicin-treated rats showed cardiac toxicity, evidenced by worsening cardiac function, evaluated by haemodynamic status and echocardiography, elevation of malondialdehyde level and a decreased level of total glutathione peroxidase activity in the heart tissue. These changes were reversed by treatment with telmisartan. Furthermore, telmisartan also downregulated matrix metalloproteinase-2 expression, attenuated the increased protein expression of p22(phox), p47(phox), p67(phox), nuclear factor kappa B and Nox4 in heart tissue, and reduced oxidative-stress-induced DNA damage, which was evaluated by the expression of 8-hydroxydeoxyguanosine. Moreover, telmisartan reduced the myocardial apoptosis induced by daunorubicin. CONCLUSIONS: The present study indicates that telmisartan may improve cardiac function by inhibiting the action of Ang II via AT-1R, which reverses oxidative stress and myocardial apoptosis. This suggests a beneficial effect of telmisartan treatment in the prevention of daunorubicin-induced cardiotoxicity.