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Previous studies have shown that the renin-angiotensin system (RAS) is activated in diabetes and this may contribute to the subcellular remodelling and heart dysfunction in this disease. Therefore, we examined the effects of RAS blockade by enalapril, an angiotensin-converting enzyme inhibitor, and losartan, an angiotensin receptor AT1 antagonist, on cardiac function, myofibrillar and myosin ATPase activity as well as myosin heavy chain (MHC) isozyme expression in diabetic hearts. Diabetes was induced in rats by a single injection of streptozotocin (65 mg/kg; i.v.) and these animals were treated with and without enalapril (10 mg/kg/day; oral) or losartan (20 mg/kg/day; oral) for 8 weeks. Enalapril or losartan prevented the depressions in left ventricular rate of pressure development, rate of pressure decay and ventricular weight seen in diabetic animals. Both drugs also attenuated the decrease in myofibrillar Ca2+-ATPase, Mg2+-ATPase and myosin ATPase activity seen in diabetic rats. The diabetes-induced increase in beta-MHC content and gene expression as well as the decrease in alpha-MHC content and mRNA levels were also prevented by enalapril and losartan. These results suggest the occurrence of myofibrillar remodelling in diabetic cardiomyopathy and provide evidence that the beneficial effects of RAS blockade in diabetes may be associated with attenuation of myofibrillar remodelling in the heart.
Mol Cell Biochem 2004 Jun
PMID:Renin-angiotensin blockade attenuates cardiac myofibrillar remodelling in chronic diabetes. 1536 13

Administration of a single high-dose (SHD) of streptozotocin (STZ) to young adult rats causes a diabetic cardiomyopathy. Albino Oxford (AO) and Dark Agouti (DA) inbred strains of rats are susceptible to developing diabetes when administered a SHD of STZ but differ in susceptibility to multiple low-dose (MLD) STZ. We have investigated the effects of SHD and MLD-STZ on contraction and intracellular Ca2+, measured with fura-2, in ventricular myocytes from AO and DA rats at 18-20 weeks after treatment. Time to peak shortening was significantly prolonged in myocytes from DA rats after SHD-STZ but was not altered in DA rats after MLD-STZ or in AO rats by either MLD or SHZ-STZ treatment. Time to peak shortening in myocytes from DA control and DA rats after SHD-STZ were 88+/-2 ms and 107+/-4 ms, respectively. Time to half relaxation and the amplitude of myocyte shortening were not altered in AO or DA rats by either MLD or SHD-STZ treatment. Amplitude, time to peak fura-2 transient and time to half relaxation of the fura-2 transient were not significantly altered in AO or DA rats by either MLD or SHD-STZ treatment. Contractile defects reported in myocytes from SHD-STZ treated DA rats may be a consequence of altered myofilament sensitivity to Ca2+. The hyperglycaemic effects of MLD-STZ and SHD-STZ induced diabetes was much greater in DA compared to AO rats and the effects of the hyperglycaemia on the time-course of ventricular myocyte contraction was most profound in DA rats after SHD-STZ.
Mol Cell Biochem 2005 Jan
PMID:Effects of single high-dose and multiple low-dose streptozotocin on contraction and intracellular Ca2+ in ventricular myocytes from diabetes resistant and susceptible rats. 1578 21

Diabetic cardiomyopathy is a common chronic complication leading to heightened risk of heart failure among diabetic patients. In this chapter, we describe the methods for maintenance and breeding of two diabetic animal models, OVE26 and Agouti mice, for type 1 and type 2 diabetes, respectively. To understand the pathological mechanism, antioxidants such as manganese superoxide dismutase are overexpressed specifically in hearts of diabetic mice. Methods utilized to produce cardiac-targeted transgenic mice are presented in this chapter. Diabetic cardiomyopathy is evaluated in control, diabetic and transgene-protected diabetic animals by measuring contractility of isolated cardiomyocytes. Preparation and contractile analysis of cardiac myocytes are described in detail. Diabetic cardiomyocytes exhibit impaired contractility as well as delayed relaxation, and cardiac-overexpressed antioxidant transgenes are shown to reverse this damage.
Methods Mol Med 2005
PMID:Cardiomyocyte defects in diabetic models and protection with cardiac-targeted transgenes. 1601 31

We previously demonstrated that chronic treatment with the mixed endothelin A and B (ET(A) and ET(B)) receptor blocker bosentan improved isolated working heart function in streptozotocin (STZ) diabetic rats. Endothelin-1 (ET-1) peptide levels, ET-1 mRNA and ET(A) and ET(B) receptor mRNA were all increased in diabetic hearts, but were unaffected by bosentan treatment, indicating that the beneficial effects of bosentan on heart appear to be on downstream effectors of ET-1 and ET receptors rather than the ET-1 system itself. Stimulation of ET-1 receptors leads to increased activation of protein kinase C (PKC), which is associated with PKC translocation from the cytosol to the membrane. Persistent activation of specific PKC isoforms has been proposed to contribute to diabetic cardiomyopathy. The purpose of this study was to determine whether chronic treatment with bosentan influences the activation of PKC isoforms in hearts from diabetic rats. Male Wistar rats were divided into four groups: control, bosentan-treated control, diabetic, and bosentan-treated diabetic. Diabetes was induced by the intravenous injection of 60 mg/kg streptozotocin. One week later, treatment with bosentan (100 mg/kg/day) by oral gavage was begun and continued for 10 weeks. The heart was then removed, homogenized, separated into soluble (cytosolic) and particulate (membrane) fractions and PKC isoform content in each fraction was determined by Western blotting. PKC alpha, beta2, delta, epsilon and zeta were all detected in hearts from both control and diabetic rats. However, no change in the levels or distribution between the soluble and particulate fractions of any of these isoforms could be detected in chronic diabetic hearts compared to control, whether untreated or treated with bosentan. These observations indicate that bosentan does not improve cardiac performance in STZ diabetic rats by affecting the activation of PKC isoforms.
Mol Cell Biochem 2006 Jan
PMID:Improvement in cardiac function of diabetic rats by bosentan is not associated with changes in the activation of PKC isoforms. 1631 25

Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury, heart transplantation, diabetic cardiomyopathy and chronic heart failure. In recent studies, we have demonstrated the beneficial effects of a novel ultrapotent PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction and remodeling in rat model of advanced aging-associated chronic heart failure and in a mouse model of heart failure induced by aortic banding. In the current study, we have investigated the effect of INO-1001 on the development of heart failure induced by permanent ligation of the left anterior descending coronary artery, heart failure induced by doxorubicin and acute myocardial dysfunction induced by bacterial endotoxin. In the coronary ligation model, a significantly depressed left ventricular performance and impaired vascular relaxation of aortic rings were found, and PARP inhibition significantly improved both cardiac function and vascular relaxation. In the doxorubicin model, a single injection of doxorubicin induced high mortality and a significant decrease in left ventricular systolic pressure, +dP/dt, -dP/dt, stroke volume, stroke work, ejection fraction and cardiac output. Treatment with the PARP inhibitor reduced doxorubicin-induced mortality and markedly improved cardiac function. PARP inhibition did not interfere with doxorubicin's antitumor effect. In the endotoxin model of cardiac dysfunction, PARP inhibition attenuated the suppression of myocardial contractility elicited by endotoxin. The current data strengthen the view that PARP inhibition may represent an effective approach for the experimental therapy of various forms of acute and chronic heart failure.
Int J Mol Med 2006 Feb
PMID:Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. 1639 39

The Otsuka-Long-Evans Tokushima Fatty rat represents a model for spontaneous non-insulin-dependent type II diabetes mellitus (DM), characterized by diastolic dysfunction and associated with abnormal calcium handling and decrease in sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) expression. The aim of this study was to examine whether SERCA2a gene transfer can restore the energetic deficiency and left ventricular (LV) function in this model. DM rats were randomized to receive adenovirus carrying either the SERCA2a gene (DM + Ad.SERCA2a) or the beta-galactosidase gene (DM + Ad.betaGal) or saline (DM + saline). LV mechanoenergetic function was measured in cross-circulated heart preparations 3 days after infection. In DM, end-systolic pressure at 0.1 ml intraballoon water (ESP0.1) was low and end-diastolic pressure at 0.1 ml intraballoon water (EDP0.1) was high (22 mm Hg), compared with non-DM (EDP0.1 12 mm Hg). In DM + Ad.SERCA2a, however, ESP0.1 was increased over 200 mm Hg and EDP(0.1) was decreased to 7 mm Hg. LV relaxation rate was fast in DM + Ad.SERCA2a, but slow in the other DM groups. There was no difference in relation between cardiac oxygen consumption per beat and systolic pressure-volume area among all groups. Finally, the oxygen cost of LV contractility in DM was about three times as high as that of normal. In DM + Ad.SERCA2a, the oxygen cost decreased to control levels, but in DM + Ad.betaGal/DM + saline it remained high. In DM failing hearts, the high oxygen cost indicates energy wasting, which contributes to the contractile dysfunction observed in diabetic cardiomyopathy. SERCA2a gene transfer transforms this inefficient energy utilization into a more efficient state and restores systolic and diastolic function to normal.
Mol Ther 2006 May
PMID:Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer. 1658 3

Hyperglycemia promotes fibrosis by increasing collagen synthesis, a process involving mitogen activated protein kinases (MAPKs). Several studies of diabetic cardiomyopathy have demonstrated an accumulation of collagen, including collagen types I and III, in the myocardium, leading to interstitial fibrosis, which is related to left-ventricular diastolic dysfunction. However, the mechanisms of hyperglycemia-induced collagen production in cardiac fibroblasts are poorly defined. In the present study, neonatal rat cardiac fibroblasts treated with high glucose (25 mM) were assessed by real time PCR and enzyme linked immunosorbent assay (ELISA) showed an increase in both the mRNA and protein level of collagen types I and III. These effects were not due to changes in osmotic pressure. Extracellular signal regulated kinase 1/2 (ERK1/2) was activated by high glucose level (25 mM), and treatment with PD98059 to block ERK phosphorylation significantly inhibited the mRNA and protein expression of collagen types I and III. These results suggest that high glucose accelerates the synthesis of collagen types I and III, and an ERK1/2 cascade in cardiac fibroblasts play an essential role in the control of collagen deposition by high glucose.
Mol Cell Biochem 2007 Jul
PMID:High glucose promotes the production of collagen types I and III by cardiac fibroblasts through a pathway dependent on extracellular-signal-regulated kinase 1/2. 1720 78

Diabetic cardiomyopathy has been documented as an underlying etiology of heart failure (HF) among diabetics. Although oxidative stress has been proposed to contribute to diabetic cardiomyopathy, much of the evidence lacks specificity. Furthermore, whether alterations occur at the cardiac proteome level in diabetic cardiac complications with attendant oxidative stress remains unknown. Therefore, we sought to identify cardiac protein changes in relation to myocardial oxidative stress that are specific to diabetic cardiomyopathy. Diabetes was induced in rats by a single injection of streptozotocin (STZ). STZ-treated rats were examined for diabetic cardiomyopathy at 8 weeks post-STZ by left ventricular (LV) hemodynamic analysis. LV systolic pressure (LVSP), rate of pressure rise (+dP/dt), and rate of pressure decay (-dP/dt) were depressed while LV end-diastolic pressure (LVEDP) was increased. Myocardial oxidative stress was increased in STZ-diabetic rats, as indexed by significant increases in myocardial formation of 8-iso PGF(2alpha) and oxidized glutathione (GSSG). In-depth mining of the diabetic myocardial proteome by proteomic analysis utilizing two-dimensional difference gel electrophoresis and mass spectrometry (DIGE/MS) techniques revealed that a high proportion (12 of 24) of the altered proteins that could be identified by mass spectrometry were localized to the mitochondria. Down-regulation of antioxidant and anti-apoptotic proteins was also observed in STZ-diabetic hearts. These results characterize a specific 'type I diabetic' pattern of cardiac proteome changes indicative of diabetic cardiomyopathy presenting with higher oxidative stress, supporting the idea that analysis of isoprostane biosynthesis and protein expression profiles may be useful diagnostically to assess the efficacy of antioxidant therapies as prophylactic treatments against type I diabetes mellitus complications involving the heart.
J Mol Cell Cardiol 2007 Apr
PMID:Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. 1732 Jan

Glucose metabolism plays an important role in cardiac bioenergetics that changes under various stress conditions including hypertrophy, diabetic cardiomyopathy, and ischemia-reperfusion injury. To understand the role of glycolysis under these conditions, we have altered several steps of the glycolytic pathway specifically in the heart. In this chapter, we describe methods used to produce cardiac-targeted transgenic mice and procedures for measuring various glucose metabolites including glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, and glycogen. Also, we describe methods for measuring glucose transport and glycolysis in perfused mouse hearts. Using these methods, we show that mice over-expressing cardiac-specific kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (Mykd-PFK-2) show reduced glucose transport and reduced glycolysis when compared with control. The metabolites glucose-6-phosphate, fructose-6-phosphate, and glycogen were elevated, whereas fructose-1,6-bisphosphate was reduced in the transgenic Mykd-PFK-2 mouse hearts.
Methods Mol Med 2007
PMID:Altering and analyzing glucose metabolism in perfused hearts of transgenic mice. 1828 70

Cardiovascular sequelae including diabetic cardiomyopathy constitute the major cause of death in diabetic patients. Although several factors may contribute to the development of this cardiomyopathy, the underlying molecular/cellular mechanisms leading to cardiac dysfunction are still partially understood. Recently, a novel paradigm for the role of the adipocytokine resistin in diabetes has emerged. Resistin has been proposed to be a link between obesity, insulin resistance and diabetes. Using microarray analysis, we have recently found that cardiomyocytes isolated from type 2 diabetic hearts express high levels of resistin. However, the function of resistin with respect to cardiac function is unknown. In this study we show that resistin is not only expressed in the heart, but also promotes cardiac hypertrophy. Adenovirus-mediated overexpression of resistin in cultured neonatal rat ventricular myocytes (NRVM) significantly increased sarcomere organization and cell size, increased protein synthesis and increased the expression of atrial natriuretic factor and beta-myosin heavy chain. Overexpression of resistin in NRVM was also associated with activation of the mitogen-activated protein (MAP) kinases, ERK1/2 and p38, as well as increased Ser-636 phosphorylation of insulin receptor substrate-1 (IRS-1), indicating that IRS-1/MAPK pathway may be involved in the observed hypertrophic response. Overexpression of resistin in adult cultured cardiomyocytes significantly altered myocyte mechanics by depressing cell contractility as well as contraction and relaxation velocities. Intracellular Ca(2+) measurements showed slower Ca(2+) transients decay in resistin-transduced myocytes compared to controls, suggesting impaired cytoplasmic Ca(2+) clearing or alterations in myofilament activation. We conclude that resistin overexpression alters cardiac contractility, confers to primary cardiomyocytes all the features of the hypertrophic phenotype and promotes cardiac hypertrophy possibly via the IRS-1/MAPK pathway.
J Mol Cell Cardiol 2008 Aug
PMID:Role of resistin in cardiac contractility and hypertrophy. 1859 75


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