Abnormal cardiac function in the streptozotocin-induced, non–insulin-dependent diabetic rat

Joffe, Ian I.; Travers, Kerry E.; Perreault‐Micale, Cynthia; Hampton, Thomas G.; Katz, Sidney; Morgan, James P.; Douglas, Pamela S.

doi:10.1016/s0735-1097(99)00436-2

Cited by 130 publications

(37 citation statements)

References 40 publications

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“…3, A-C, and Table III). In accordance with previous findings in rats (11,15), the heart rate was slightly decreased in STZ-treated mice, although this effect was not statistically significant. The indexes of systolic function (e.g.…”

Section: Effects Of Diabetes and Apob Overexpression On Cardiac Functsupporting

confidence: 92%

“…Diabetes is associated with aberrations in cardiac fuel metabolism and a ϳ2-fold increase in cardiac triglyceride content (9, 10). In diabetic rats, this triglyceride accumulation occurs in parallel with compromised cardiac performance (11,12). Echocardiographic studies have also revealed abnormal cardiac function in young diabetic individuals without coronary heart disease (13).…”

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confidence: 99%

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Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice

Nielsen¹,

Bartels²,

Bollano³

2002

Journal of Biological Chemistry

128

109

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The heart secretes apolipoprotein B (apoB) containing lipoproteins. Herein, we examined whether the overexpression of a human apoB transgene in the heart affects triglyceride accumulation and development of cardiac dysfunction in streptozotocin-treated diabetic mice. Blood glucose, plasma free fatty acids, and plasma triglycerides were similarly affected in diabetic wild type mice and diabetic apoB transgenic mice as compared with non-diabetic mice of the same genotype. After 12 weeks, heart triglycerides were increased by 48% in diabetic wild type mice. These mice displayed an increased expression of brain natriuretic peptide and deterioration of heart function on echocardiography. In diabetic apoB transgenic mice, heart triglyceride levels were identical to those in non-diabetic wild type and apoB transgenic mice, and brain natriuretic peptide expression as well as echocardiographic indexes of heart function were only marginally affected or unaffected. The findings suggest that triglyceride accumulation in the heart is important for development of diabetic cardiomyopathy in mice, and that lipoprotein formation by cardiomyocytes plays an integrated role in cardiac lipid metabolism.Liver and intestinal cells secrete triglyceride-rich lipoproteins. This ability is dependent on the expression of the apoB and microsomal triglyceride transfer protein (MTP) 1 genes (1, 2). MTP transfers triglycerides onto the apoB polypeptide chain during its translation into the endoplasmic reticulum. ApoB serves as the principal structural protein in the resulting lipoprotein particles that are secreted from the cells. Studies of mice, which overexpress a human apoB transgene, revealed that cardiac myocytes in addition to hepatocytes and absorptive enterocytes also express the apoB and MTP genes (3) and secrete apoB containing lipoproteins (4). The apoB mRNA is not edited in cardiac myocytes (5). Consequently, the heart secretes lipoproteins containing the full-length apoB100 protein rather than the truncated apoB48 protein (4). Because the formation of apoB-containing lipoproteins serves as an effective means of secreting large amounts of triglycerides from liver and intestinal cells, we hypothesized previously that the physiological role of lipoprotein formation in the heart could be the removal of triglycerides from myocytes that are not used as fuel, i.e. a reverse triglyceride transport pathway (6, 7).Recently, the idea has been put forward that triglyceride accumulation in cardiac muscle cells adversely affects cardiac function (8). Diabetes is associated with aberrations in cardiac fuel metabolism and a ϳ2-fold increase in cardiac triglyceride content (9, 10). In diabetic rats, this triglyceride accumulation occurs in parallel with compromised cardiac performance (11,12). Echocardiographic studies have also revealed abnormal cardiac function in young diabetic individuals without coronary heart disease (13). It is unknown as to what extent triglyceride accumulation in cardiac myocytes affects the development of diabetes-ind...

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Section: Effects Of Diabetes and Apob Overexpression On Cardiac Functsupporting

confidence: 92%

mentioning

confidence: 99%

Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice

Nielsen¹,

Bartels²,

Bollano³

2002

Journal of Biological Chemistry

128

109

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“…The mechanism of diastolic dysfunction remains unknown but it does not appear to be due to changes in blood pressure, microvascular complications or elevated circulating glycated hemoglobin levels [78][79][80][81][82]. There is circumstantial clinical and experimental evidence suggesting that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia/functional hypoxia, and elevated circulating levels of glucose result in oxidative and nitrosative stress in cardiovascular system of diabetic animals and humans.…”

Section: The Role Of Oxidative and Nitrosative Stress In The Pathogenmentioning

confidence: 99%

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

Pacher

Obrosova

Mabley

et al. 2005

CMC

308

243

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Macro-and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.

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“…STZ-induced diabetic rats develop a cardiomyopathy that is characterized by decreased left ventricular (LV) contractility, diminished ventricular compliance with markedly abnormal diastolic function, and decreased inotropic and chronotropic responses to certain ligands (9,10). The abnormalities in diastolic function in diabetic rats are manifested by prolonged isovolumic relaxation time, increased atrial contribution to diastolic filling, and elevated in vivo LV end-diastolic pressure (10). STZ-induced diabetic rats do not develop atherosclerosis or hypertension, so the cardiomyopathy is presumably caused by a direct effect of diabetes on the cardiac myocyte.…”

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confidence: 99%

G-Protein Signaling Participates in the Development of Diabetic Cardiomyopathy

et al. 2004

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Diabetic patients develop a cardiomyopathy that consists of ventricular hypertrophy and diastolic dysfunction. Although the pathogenesis of this condition is poorly understood, previous studies implicated abnormal G-protein activation. In this work, mice with cardiac overexpression of the transcription factor peroxisome proliferator-activated receptor-␣ (PPAR-␣) were examined as a model of diabetic cardiomyopathy. PPAR-␣ transgenic mice develop spontaneous cardiac hypertrophy, contractile dysfunction, and "fetal" gene induction. We examined the role of abnormal G-protein activation in the pathogenesis of cardiac dysfunction by crossing PPAR-␣ mice with transgenic mice with cardiac-specific overexpression of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G q and G i . Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-␣ overexpression without affecting the metabolic abnormalities seen in these hearts. Next, transgenic mice with increased or decreased cardiac G q signaling were made diabetic by injection with streptozotocin (STZ). RGS4 transgenic mice were resistant to STZ-induced cardiac fetal gene induction. Transgenic mice with cardiac-specific expression of mutant G ␣q , G ␣q -G188S, that is resistant to RGS protein action were sensitized to the development of STZ-induced cardiac fetal gene induction and bradycardia. These results establish that G q -mediated signaling plays a critical role in the pathogenesis of diabetic cardiomyopathy. Diabetes 53:3082-3090, 2004 B oth insulin-dependent (type 1) and non-insulindependent (type 2) forms of diabetes in humans are accompanied by a greatly increased risk of cardiovascular death (1-3). Both types of diabetes are associated with cardiomyopathy that share many similar characteristics, including ventricular hypertrophy, decreased ventricular diastolic relaxation, and a reduced peak filling rate (4 -7). Diabetic cardiomyopathy is distinct from ischemic cardiomyopathy because it is present in diabetic patients and animal models of diabetes in the absence of coronary artery disease.Recently, rodent models of diabetes were used to uncover the pathogenesis of diabetic cardiomyopathy. One animal model of diabetic cardiomyopathy was developed that consists of cardiac-specific overexpression of the transcription factor myosin heavy chain (MHC)-peroxisome proliferator-activated receptor-␣ (PPAR-␣) (8). PPAR-␣ is a ligand-activated transcription factor that regulates genes involved in cardiac fatty acid uptake and oxidation. PPAR-␣ is activated in the diabetic heart (8). MHC-PPAR transgenic mice develop a metabolic phenotype that is similar to the diabetic state in the heart but not in other tissues, with increased lipid uptake and oxidation and reduced glucose uptake and oxidation (8). Furthermore, MHC-PPAR mice develop a cardiomyopathy with ventricular hypertrophy, activation of gene markers of pathological hypertrophic growth, and...

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Abnormal cardiac function in the streptozotocin-induced, non–insulin-dependent diabetic rat

Abstract: Diabetic cardiomyopathy is characterized by LV systolic and diastolic dysfunction, the latter correlating with decreased exhaled NO. The NO pathway is intact, suggesting impaired availability of NO as contributor to cardiomyopathy.

Cited by 130 publications

References 40 publications

Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice

Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice

Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

G-Protein Signaling Participates in the Development of Diabetic Cardiomyopathy

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