atrial-natriuretic-factor and Diabetic-Cardiomyopathies

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes that emphasizes the urgency of developing new drug therapies. With an illustrious history in traditional medicine to improve diabetes, cinnamon has been shown to possess blood lipids lowering effects and antioxidative and anti-inflammatory properties. However, the extent to which it protects the diabetic heart has yet to be determined. Forty-eight rats were administered in the study and grouped as: control; diabetic; diabetic rats given 100, 200, or 400 mg/kg cinnamon extract, metformin (300 mg/kg), valsartan (30 mg/kg), or met/val (combination of both drugs), via gavage for six weeks. Fasting blood sugar (FBS) and markers of cardiac injury including creatine kinase-muscle/brain (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were evaluated in blood samples. Malondialdehyde (MDA) levels, the total contents of thiol, superoxide dismutase (SOD), and catalase (CAT) activities were measured. Histopathology study and gene expression measurement of angiotensin II type 1 receptor (AT1), atrial natriuretic peptide (ANP), beta-myosin heavy chain (β-MHC), and brain natriuretic peptide (BNP) were done on cardiac tissue. FBS and cardiac enzyme indicators were reduced in all treated groups. A reduction in MDA level and enhancement in thiol content alongside with increase of SOD and CAT activities were observed in extract groups. The decrease of inflammation and fibrosis was obvious in treated groups, notably in the high-dose extract group. Furthermore, all treated diabetic groups showed a lowering trend in AT1, ANP, β-MHC, and BNP gene expression. Cinnamon extract, in addition to its hypoglycemic and antioxidant properties, can prevent diabetic heart damage by alleviating cardiac inflammation and fibrosis. PRACTICAL APPLICATIONS: This study found that cinnamon extract might protect diabetic heart damage by reducing inflammation and fibrosis in cardiac tissue, in addition to lowering blood glucose levels and increasing antioxidant activity. Our data imply that including cinnamon in diabetic participants' diets may help to reduce risk factors of cardiovascular diseases.

Topics: Animals; Antioxidants; Atrial Natriuretic Factor; Cinnamomum zeylanicum; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Heart Injuries; Humans; Hypertrophy; Inflammation; Plant Extracts; Rats; Sulfhydryl Compounds; Superoxide Dismutase

Cardiac hypertrophy is a key pathological process in the context of diabetic cardiomyopathy. Naringenin exhibits multiple pharmacological activities, but the effect of naringenin on cardiomyocyte hypertrophy under diabetic conditions is still far from clear.. Cardiomyocyte hypertrophy was induced by high glucose (HG, glucose at 25.5 mmol/L) in H9c2 cells, which was determined by cell surface area, protein content and atrial natriuretic factor (ANF) mRNA expression. The effect of naringenin on cardiomyocyte hypertrophy was observed and its mechanisms were investigated by administration with various inhibitors on epoxyeicosatrienoic acids (EETs)/peroxisome proliferator-activated receptors (PPARs). The level of 14,15-EET was measured by ELISA. The mRNA and protein expressions were detected by qRT-PCR or Western blot, respectively.. Naringenin (0.1, 1, 10 μmol/L) inhibited cardiomyocyte hypertrophy in a concentration-dependent manner (P < 0.05), up-regulated the expressions of PPARα, PPARβ, PPARγ and CYP2J3 (P < 0.05), and increased the level of 14,15-EET (P < 0.05). PPOH, a CYP2J3 inhibitor, blocked the naringenin-mediated improvement of myocardial hypertrophy (P < 0.01), and abolished the up-regulation of PPARs expressions (P < 0.01). Meanwhile, MK886, a PPARα antagonist, GSK0660, a PPARβ antagonist, and GW9662, a PPARγ antagonist, reversed the protection of naringenin on cardiomyocytes (P < 0.05), and abrogated the up-regulation of CYP2J3-EET produced by naringenin (P < 0.05).. Activation of EETs and PPARs function together may be contributed to the anti-hypertrophic effect of naringenin in H9c2 cells under high glucose condition.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Cell Line; Diabetic Cardiomyopathies; Flavanones; Glucose; Myocytes, Cardiac; PPAR gamma; Rats; RNA, Messenger; Signal Transduction; Up-Regulation

A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Cell Line; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Eicosanoids; Epoxide Hydrolases; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Natriuretic Peptide, Brain; Obesity; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Signal Transduction; Streptozocin

Diabetes mellitus (DM) has been demonstrated to have a strong association with heart failure. Conventional echocardiographic analysis cannot sensitively monitor cardiac dysfunction in type I diabetic Akita hearts, but the phenotype of heart failure is observed in molecular levels during the early stages.. Male Akita (Ins2WT/C96Y) mice were monitored with echocardiographic imaging at various ages, and then with conventional echocardiographic analysis and speckle-tracking based strain analyses.. With speckle-tracking based strain analyses, diabetic Akita mice showed changes in average global radial strain at the age of 12 weeks, as well as decreased longitudinal strain. These changes occurred in the early stage and remained throughout the progression of diabetic cardiomyopathy in Akita mice. Speckle-tracking showed that the detailed and precise changes of cardiac deformation in the progression of diabetic cardiomyopathy in the genetic type I diabetic Akita mice were uncoupled.. We monitored early-stage changes in the heart of diabetic Akita mice. We utilize this technique to elucidate the underlying mechanism for heart failure in Akita genetic type I diabetic mice. It will further advance the assessment of cardiac abnormalities, as well as the discovery of new drug treatments using Akita genetic type I diabetic mice.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Disease Models, Animal; Echocardiography; Female; Heart; Heart Rate; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocardium; Natriuretic Peptide, Brain; Severity of Illness Index; Ventricular Dysfunction, Left

Cardiac injury, including hypertrophy and fibrosis, induced by advanced glycation end products (AGEs) has an important function in the onset and development of diabetic cardiomyopathy. Profilin‑1, a ubiquitously expressed and multifunctional actin‑binding protein, has been reported to be an important mediator in cardiac hypertrophy and fibrosis. However, whether profilin‑1 is involved in AGE‑induced cardiac hypertrophy and fibrosis remains to be determined. Therefore, the present study aimed to investigate the function of profilin‑1 in cardiac injury induced by AGEs. The model of cardiac injury was established by chronic tail vein injection of AGEs (50 mg/kg/day for 8 weeks) in Sprague‑Dawley rats. Rats were randomly assigned to control, AGEs, AGEs + profilin‑1 shRNA adenovirus vectors (AGEs + S)or AGEs + control adenovirus vectors (AGEs + V) groups. Profilin‑1 shRNA adenovirus vectors were injected via the tail vein to knockdown profilin‑1 expression at a dose of 3x109 plaque forming units every 4 weeks. Echocardiography was performed to measure cardiac contractile function. Cardiac tissues were stained with Masson's trichrome stain to evaluate ventricular remodeling. The serum levels of procollagen type III N‑terminal peptide were detected by ELISA. The expression of profilin‑1, receptor for AGEs (RAGE), Rho, p65, atrial natriuretic peptide, β‑myosin heavy chain, matrix metalloproteinase (MMP)‑2 and MMP‑9 were determined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and/or western blot analysis and immunohistochemistry staining. The results demonstrated that chronic injection of exogenous AGEs led to cardiac dysfunction, hypertrophy and fibrosis, as determined by echocardiography, Masson trichrome staining and the expression of associated genes. The expression of profilin‑1 was markedly increased in heart tissue at the mRNA and protein level following AGE administration, as determined by RT‑qPCR and western blotting, which was further confirmed by immunohistochemistry staining. Furthermore, the expression of RAGE, Rho and p65 was also increased at the protein level. Notably, knockdown of profilin‑1 expression ameliorated AGE‑induced cardiac injury and reduced the expression of RAGE, Rho and p65. These results indicate an important role for profilin‑1 in AGE‑induced cardiac injury, which may provide a novel therapeutic target for patients with diabetic heart failure.

Topics: Adenoviridae; Animals; Atrial Natriuretic Factor; Collagen Type III; Diabetic Cardiomyopathies; Echocardiography; Fibrosis; Glycation End Products, Advanced; Heart; Heart Injuries; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Profilins; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; RNA, Small Interfering

Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism.. H9c2 myocardial cells were treated with tropisetron or cyclosporine A 1 h before exposure to HG for 48 h.. Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca(2+) level, calcineurin expression and nuclear translocation of NFATc4. Both tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca(2+) was not affected.. Our results showed that tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway.

Topics: Active Transport, Cell Nucleus; Animals; Atrial Natriuretic Factor; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiomegaly; Cell Line; Cell Size; Cytoprotection; Diabetic Cardiomyopathies; Glucose; Indoles; Myocytes, Cardiac; Nerve Tissue Proteins; NFATC Transcription Factors; Rats; Signal Transduction; Tropisetron

Cardiac hypertrophy and myocardial fibrosis significantly contribute to the pathogenesis of diabetic cardiomyopathy (DCM). Altered expression of several genes and their regulation by microRNAs has been reported in hypertrophied failing hearts. This study aims to examine the role of Cdc42, Pak1, and miR-30c in the pathogenesis of cardiac hypertrophy in DCM.. DCM was induced in Wistar rats by low-dose streptozotocin-high-fat diet for 12 weeks. Cardiac expression of Cdc42, Pak1 and miR-30c, and hypertrophy markers (ANP and β-MHC) was studied in DCM vs control rats and in high-glucose (HG)-treated H9c2 cardiomyocytes.. Diabetic rats showed cardiomyocyte hypertrophy, increased heart-to-body weight ratio, and an increased expression of ANP and β-MHC. Cardiac expression of Cdc42 and Pak1 genes was increased in diabetic hearts and in HG-treated cardiomyocytes. miR-30c was identified to target Cdc42 and Pak1 genes, and cardiac miR-30c expression was found to be decreased in DCM rats, patients with DCM, and in HG-treated cardiomyocytes. miR-30c overexpression decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas miR-30c inhibition increased Cdc42 and Pak1 gene expression and myocyte hypertrophy in HG-treated cardiomyocytes.. Downregulation of miR-30c mediates prohypertrophic effects of hyperglycemia in DCM by upregulation of Cdc42 and Pak1 genes.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Myosins; Cardiomegaly; cdc42 GTP-Binding Protein; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; MicroRNAs; Myocytes, Cardiac; Myosin Heavy Chains; p21-Activated Kinases; Rats; Rats, Wistar; Streptozocin; Up-Regulation

Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM.. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague-Dawley rats (180-220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson's trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay.. The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats.. Our results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Down-Regulation; Immunohistochemistry; Myocardium; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Serine Endopeptidases; Wound Healing

The combination of systemic arterial hypertension and diabetes mellitus (DM) induces greater cardiac remodeling than either condition alone. However, this association has been poorly addressed in senescent rats. Therefore, this study aimed to analyze the influence of streptozotocin-induced DM on ventricular remodeling and oxidative stress in aged spontaneously hypertensive rats (SHR).. Fifty 18 month old male SHR were divided into two groups: control (SHR, n = 25) and diabetic (SHR-DM, n = 25). DM was induced by streptozotocin (40 mg/kg, i.p.). After nine weeks, the rats underwent echocardiography and myocardial functional study in left ventricular (LV) isolated papillary muscle preparations. LV samples were obtained to measure myocyte diameters, interstitial collagen fraction, and hydroxyproline concentration. Gene expression of atrial natriuretic peptide (ANP) and α- and β-myosin heavy chain (MyHC) isoforms was evaluated by RT-PCR. Serum oxidative stress was assessed by measuring lipid hydroperoxide concentration and superoxide dismutase and glutathione peroxidase activities.. Student's t test or Mann-Whitney test, p < 0.05.. SHR-DM presented higher blood glucose (487 ± 29 vs. 89.1 ± 21.1 mg/dL) and lower body weight (277 ± 26 vs. 339 ± 38 g). Systolic blood pressure did not differ between groups. Echocardiography showed LV and left atrial dilation, LV diastolic and relative wall thickness decrease, and LV systolic and diastolic function impairment in SHR-DM. Papillary muscle study showed decreased myocardial contractility and contractile reserve in SHR-DM. Myocyte diameters and myocardial interstitial collagen fraction and hydroxyproline concentration did not differ between groups. Increased serum pro-oxidant activity and gene expression of ANP and β/α-MyHC ratio were observed in DM.. Diabetes mellitus induces cardiac dilation and functional impairment, increases oxidative stress and activates fetal gene program in aged spontaneously hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Myosins; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Echocardiography; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Myosin Heavy Chains; Oxidative Stress; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Transcriptome; Ventricular Remodeling

Ginseng (Araliaceae) has multiple pharmacological actions because of its diverse phytochemical constituents. The aims of the present study are to evaluate the preventive effects of North American ginseng on diabetic retinopathy and cardiomyopathy and to delineate the underlying mechanisms of such effects. Models of both type 1 (C57BL/6 mice with streptozotocin-induced diabetes) and type 2 diabetes (db/db mice) and age-matched and sex-matched controls were examined. Alcoholic ginseng root (200 mg/kg body weight, daily oral gavage) extract was administered to groups of both type 1 and type 2 diabetic mice for 2 or 4 months. Dysmetabolic state in the diabetic mice was significantly improved by ginseng treatment. In both the heart and retina of diabetic animals, ginseng treatment significantly prevented oxidative stress and diabetes-induced upregulations of extracellular matrix proteins and vasoactive factors. Ginseng treatment in the diabetic animals resulted in enhancement of stroke volume, ejection fraction, cardiac output, and left ventricle pressure during systole and diastole and diminution of stroke work. In addition, mRNA expressions of atrial natriuretic factor and brain natriuretic factor (molecular markers for cardiac hypertrophy) were significantly diminished in ginseng-treated diabetic mice. These data indicate that North American ginseng prevents the diabetes-induced retinal and cardiac biochemical and functional changes probably through inhibition of oxidative stress.

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Retinopathy; Extracellular Matrix Proteins; Heart; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Oxidative Stress; Panax; Phytotherapy; Plant Extracts; Plant Roots; Retina