Inhibition of Nitric Oxide Synthase byL-NAME Improves Ventricular Performance in Streptozotocin- diabetic Rats

Smith, Jacquelyn M.; Paulson, Dennis J.; Romano, Fred D.

doi:10.1006/jmcc.1997.0474

Cited by 49 publications

(33 citation statements)

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“…This was significant for both heart rate and contractility. This result is consistent with the reduced responsiveness of diabetic hearts to beta adrenergic stimulation that has been established for several decades [35,36]. The reduced isoproterenol response of OVE26 hearts may at least partially explain why basal diabetic cardiac contractility measured by echocardiography appeared unimpaired, while contractility of isolated OVE26 myocytes was significantly impaired.…”

Section: Discussionsupporting

confidence: 85%

Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

Song

Du²,

Prabhu³

et al. 2007

Rev Diabet Stud

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■ AbstractMany diabetic patients suffer from a cardiomyopathy that cannot be explained solely by poor coronary perfusion. This cardiomyopathy may be due to either organ-based damage like fibrosis, or to direct damage to cardiomyocytes. Mitochondrial-derived reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. To address these questions, we used the OVE26 mouse model of severe type 1 diabetes to measure contractility in isolated cardiomyocytes by edge detection and in vivo with echocardiography. We also assessed the source of ROS generation using both a general and a mitochondrial specific indicator. When contractility was assayed in freshly isolated myocytes, contraction was much stronger in control myocytes. However, contractility of normal myocytes became weaker during 24 hours of in vitro culture. In contrast, contractility of diabetic OVE26 myocytes remains stable during culture. Echocardiography revealed normal or hyperdynamic function in OVE26 hearts under basal conditions but with a sharply reduced response to isoproterenol, a β-adrenergic agonist. For ROS generation, we found that ROS production in diabetic myocytes was elevated after exposure to either high glucose or angiotensin II (AngII). Superoxide detection with the mitochondrial sensor MitoSOX Red confirmed that mitochondria are a major source of ROS generation in diabetic myocytes. These results show that contractile deficits in OVE26 diabetic hearts are due primarily to cardiomyocyte impairment and that ROS from mitochondria are a cause of that impairment.

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Section: Discussionsupporting

confidence: 85%

Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

Song

Du²,

Prabhu³

et al. 2007

Rev Diabet Stud

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“…Our findings stress the impact of RAGE in generation of iNOS and nitrite and nitrate and cGMP, especially consequent to I/R. In rats rendered diabetic with STZ, the impact of diabetes and NOS in the heart was demonstrated by the beneficial effects of L-NAME (L-N G -nitro-L-arginine methyl ester) in improvement of ventricular performance (42). Our findings extend these concepts to link RAGE in the diabetic rat heart and RAGE signaling in either mononuclear phagocyte or endothelial cells in the diabetic mouse heart to iNOS expression and enhanced injury in I/R, as measured by LDH release.…”

Section: Rage and Nosmentioning

confidence: 52%

RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium

et al. 2008

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OBJECTIVE-Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues.In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.RESEARCH DESIGN AND METHODS-To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R. RESULTS-Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.CONCLUSIONS-These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart. Diabetes 57: [1941][1942][1943][1944][1945][1946][1947][1948][1949][1950][1951] 2008 C ardiac complications remain a leading cause of morbidity and mortality in subjects with diabetes (1-3). Although many factors contribute to depressed cardiac function in diabetes, innate disturbances within the diabetic heart contribute importantly to progressive dysfunction, which often leads to irreversible failure and death (3). Alterations in substrate metabolism and increased levels of oxygen free radicals have been observed in diabetic tissues. Inflammatory cytokines may exert direct negative inotropic effects on cardiac myocytes and contribute to aberrant remodeling in the failed heart (4 -8). The pathophysiology of diabetesassociated cardiac complications is complex and involves a host of factors linked to metabolic and immune/inflammatory cell activation.The accumulation of late-stage glycoxidation adducts of proteins, termed advanced glycation end products (AGEs), occurs in diabetic tissues. AGEs modify long-lived molecules in the blood vessel wall and structural tissues of the heart considerably earlier than symptomatic cardiac dysfunction occurs (9). A major way in which AGEs exert their cellular effects is by ligation of the multiligand receptor for AGE (RAGE) (10 -13).We tested the role of RAGE in rodent models of type 1 dia...

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“…Thus, increased Cu II plays a role in the deterioration of systolic function in diabetes. Peak ϪdP LV /dt is the maximum rate of fall in LV pressure during the cardiac cycle and a measure of diastolic dysfunction (31). Decreased ϪdP LV /dt reflects increased stiffness of the LV wall, which may be associated with increased content (32,33) and altered three-dimensional organization (33) of fibrous connective tissue structures such as those formed by collagen.…”

Section: Figmentioning

confidence: 99%

Regeneration of the Heart in Diabetes by Selective Copper Chelation

et al. 2004

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Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu II -trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and ␤ 1 integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

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Inhibition of Nitric Oxide Synthase byL-NAME Improves Ventricular Performance in Streptozotocin- diabetic Rats

Cited by 49 publications

References 0 publications

Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium

Regeneration of the Heart in Diabetes by Selective Copper Chelation

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