fumarates and Cardiomyopathies

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Cardiomyopathies; Collagen; Diet; Extracellular Matrix; Fibroblasts; Fibrosis; Fumarates; Homocysteine; Mice; Myocardium; Proto-Oncogene Proteins c-akt; Renin; Renin-Angiotensin System; Signal Transduction

Doxorubicin (DXR) is one of the most effective antineoplastic agents. However, the optimal clinical use of this agent is limited because of marked cardiomyopathy and congestive heart failure. Renin angiotensin system (RAS) plays an important role in the development of cardiac hypertrophy, reperfusion injury and congestive heart failure. Aliskiren (ALK) is a direct inhibitor of renin and does not affect other systems involved in cardiovascular regulation. This study was designed to explore the possible protective effects of ALK (30 and 100 mg/kg, per oral [p.o.] respectively for 42 days) in chronic model of DXR (1.25 mg/kg, intraperitoneally (i.p.) sixteen equal cumulative doses) induced cardiomyopathy in rats. DXR treatment significantly (P<0.01) increased the activities of serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiomyocyte caspase-3 and catalase (CAT). ALK (100 mg/kg) treatment prevented the animals significantly (P<0.01) from rise in the above indices. Furthermore ALK (100 mg/kg) significantly restores the DXR-induced decrease in antioxidant defense, reduced glutathione (GSH) and superoxide dismutase (SOD). Transmission electron microscopic studies showed that DXR caused apoptosis in myocardium, manifested as condensation of chromatin network at the margins and rupture of nuclear membrane which was well protected by ALK (100 mg/kg) treatment. The present study indicates that ALK protected rats from DXR-induced cardiomyopathy.

Topics: Amides; Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cardiomyopathies; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Fumarates; Microscopy, Electron, Transmission; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Aliskiren is the first in a new class of orally active direct renin inhibitors, approved for the treatment of hypertension. However, the efficacy of aliskiren in diabetic cardiovascular complications remains to be defined. This study aimed to test the hypothesis that aliskiren may enhance the beneficial effects of pioglitazone against cardiovascular injury associated with diabetic nephropathy.. Diabetic nephropathy was induced in rats by unilateral nephrectomy followed by streptozotocin injection. Diabetic nephropathic rats were orally given vehicle, pioglitazone, aliskiren, or combined pioglitazone and aliskiren for four weeks to compare their effects on cardiovascular injury, particularly myocardial fibrosis.. Pioglitazone treatment significantly attenuated cardiac lipid peroxidation, oxidative injury and myocardial fibrosis in diabetic nephropathic rats. This was associated with up-regulation of transforming growth factor-β1 and matrix metalloproteinase-2 genes, along with down-regulation of tissue inhibitor of metalloproteinase-2 gene in cardiac tissue. The combination of aliskiren with pioglitazone exerted greater beneficial effect than monotherapy with either drug, on all the aforementioned parameters.. Our findings suggested that aliskiren enhanced the protective effects of pioglitazone against myocardial fibrosis, in experimental diabetic nephropathy. Thus, the combination of aliskiren and pioglitazone may be a potential therapeutic strategy for cardiovascular injury associated with diabetic nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Fumarates; Gene Expression Regulation; Hypoglycemic Agents; Lipid Peroxidation; Male; Matrix Metalloproteinase 2; Myocardium; Nephrectomy; Oxidative Stress; Pioglitazone; Rats; Rats, Wistar; Streptozocin; Thiazolidinediones; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta1

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (PERK1/2) and matrix metalloproteinase 9 (MMP-9). In the DOC group and ALI group, the CVF and PVCA were significantly increased; the RA and Ang II levels in the plasma and ventricle were remarkably lowered when compared with the CON group. The RA and Ang II levels in the ventricle of the ALI group were significantly lower than those in the DOC group. Moreover, the expressions of ERK1/2, PERK1/2 and MMP9 were the lowest in the CON group, but those in the ALI group were significantly reduced as compared to the DOC group. ALI can inhibit the DOCA induced myocardial fibrosis independent of its pressure-lowing effect, which may be related to the suppression of RA and Ang II production, inhibition of ERK1/2 phosphorylation and MMP9 expression in the heart.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Blotting, Western; Cardiomyopathies; Cardiotonic Agents; Collagen; Desoxycorticosterone; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Fumarates; Heart Ventricles; Indicators and Reagents; Male; Matrix Metalloproteinase 9; Myocardium; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Renin

In this study, effect of aliskiren (ALK) on doxorubicin (DXR)-induced cardiomyopathy in rats was evaluated. ALK (50 and 100 mg/kg/day) was administered for 7 days and a single intraperitoneal injection of DXR (20 mg/kg) on day 5. The animals were sacrificed 48 h after DXR administration. DXR produced significant elevation in malondialdehyde (MDA) and significantly inhibited the activity of glutathione (GSH) in heart tissue, with a significant rise in the serum levels of lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and reduction in high-density lipoprotein (HDL), indicating acute cardiac toxicity. ALK pretreatment significantly reduced the MDA concentration and ameliorated the inhibition of cardiac GSH activity. ALK also significantly improved the serum levels of LDH, TC, TG, LDL and reduction in HDL in DXR-treated rats. Furthermore, histological examination of the heart sections confirmed the myocardial injury with DXR administration and the near-normal pattern with ALK pretreatment. The results provide clear evidence that the ALK pretreatment offered significant protection against DXR-induced enzymatic changes and cardiac tissue damage.

Topics: Amides; Animals; Antibiotics, Antineoplastic; Cardiomyopathies; Doxorubicin; Fumarates; Lipid Peroxidation; Lipids; Myocardium; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Topics: Alanine; Aminooxyacetic Acid; Animals; Cardiomyopathies; Fumarates; Glutamates; Hypoxia; Ketoglutaric Acids; Lactates; Malates; Mitochondria, Heart; Myocardium; Papillary Muscles; Rabbits; Succinates

Topics: Adult; Appetite Depressants; Cardiac Catheterization; Cardiomyopathies; Electrocardiography; Female; Fumarates; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Artery