Depressed Levels of Ca2+-Cycling Proteins May Underlie Sarcoplasmic Reticulum Dysfunction in the Diabetic Heart

Netticadan, Thomas; Temsah, Rana M.; Kent, A.F. Stanley; Elimban, Vijayan; Dhalla, Naranjan S.

doi:10.2337/diabetes.50.9.2133

Cited by 113 publications

(98 citation statements)

References 35 publications

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“…The protein content of SR Ca 2ϩ -cycling proteins SERCA2a and PLB and its phosphorylated forms, serine-16 PLB and threonine-17 PLB, were determined by Western blot analysis as described previously (27,28,40). SR samples (20 g) were separated by SDS-polyacrylamide gel electrophoresis on 10% (for SERCA2a) and 15% (for PLB, serine-16 PLB, and threonine-17 PLB) gels and transferred to polyvinylidene difluoride membranes.…”

Section: Inset)mentioning

confidence: 99%

Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation

Babick¹,

Cantor²,

Babick³

et al. 2004

American Journal of Physiology-Cell Physiology

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. Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation. Am J Physiol Cell Physiol 287: C1202-C1208, 2004. First published June 30, 2004 doi:10.1152/ajpcell.00155.2004.-Although dilated cardiomyopathy (DCM) is known to result in cardiac contractile dysfunction, the underlying mechanisms are unclear. The sarcoplasmic reticulum (SR) is the main regulator of intracellular Ca 2ϩ required for cardiac contraction and relaxation. We therefore hypothesized that abnormalities in both SR function and regulation will contribute to cardiac contractile dysfunction of the J2N-k cardiomyopathic hamster, an appropriate model of DCM. Echocardiographic assessment indicated contractile dysfunction, because the ejection fraction, fractional shortening, cardiac output, and heart rate were all significantly reduced in J2N-k hamsters compared with controls. Depressed cardiac function was associated with decreased cardiac SR Ca 2ϩ uptake in the cardiomyopathic hamsters. Reduced SR Ca 2ϩ uptake could be further linked to a decrease in the expression of the SR Ca 2ϩ -ATPase and cAMPdependent protein kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16. Depressed PLB phosphorylation was paralleled with a reduction in the activity of SR-associated PKA, as well as an elevation in protein phosphatase activity in J2N-k hamster. The results of this study suggest that an alteration in SR function and its regulation contribute to cardiac contractile dysfunction in the J2N-k cardiomyopathic hamster. sarcoplasmic reticulum; cardiomyopathy; cAMP-dependent protein kinase; Ca 2ϩ /calmodulin-dependent protein kinase; sarco(endo)plasmic reticulum ATPase; phospholamban CARDIOMYOPATHY is defined as a disease of the heart muscle. It is classified as one of the most critical health disorders that cause death and disability among children and adults (10,39,41). Major health problems that have been documented as a result of cardiomyopathy are thromboembolism, arrhythmia, and sudden cardiac death (7,9,10,14,19,36,39,41). As a result of its various maladies, the heart in its diseased state can show pathophysiological changes at the level of myocardium function, chamber remodeling, neurohormonal activation, and altered loading conditions (7,9,10,14,19,36,39,41). Dilated cardiomyopathy (DCM) is a form of cardiomyopathy that is characterized by chamber dilation and impaired cardiac pump function. Although DCM is known to result in cardiac contractile dysfunction, the underlying mechanisms are unclear. In this study we examined the mechanisms underlying contractile dysfunction in cardiomyopathic hamsters, an excellent model of DCM. The Japanese J2N-k cardiomyopathic hamster was used because it uniquely exhibits a deletion in the ␦-sarcoglycan gene located in striated muscle, thereby affecting both skeletal and cardiac entities (25, 32). These hamsters experience cardiomyopathy, in addition to a form of muscular dystrophy, with eventual progression into heart failure (23). This an...

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Section: Inset)mentioning

confidence: 99%

Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation

Babick¹,

Cantor²,

Babick³

et al. 2004

American Journal of Physiology-Cell Physiology

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“…Accordingly the attenuation of arrhythmias in late stage of diabetes may be related to a reduction in CaM KII activity. However, some of our earlier observations (18,37) have reported that although SR CaM KII activity is increased in the diabetic (6-wks post STZ-induced diabetes) heart, it is decreased in 10 wks sucrose-fed rats (38). Therefore, it appears that changes in CaM KII activity are biphasic in nature and dependent on the stage or severity of diabetes.…”

Section: Dose Of Epimentioning

confidence: 87%

Susceptibility of Diabetic Heart to Catecholamine-induced Arrhythmias is Independent of Contractile Dysfunction

Adameová

Elimban²,

Rodriguez-Leyva

et al. 2014

Serbian Journal of Experimental and Clinical Research

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Background: Diabetes is associated with myocardial electrical instability and prolongation of action potential duration that result in disturbances in the rhythm of the heart. Objective: Th is study was undertaken to examine the role of circulating catecholamines in abnormal cardiac rhythm and contractility during diff erent stages of diabetes. Methods: Diabetes was induced in male Sprague-Dawley rats with streptozotocin (STZ; 65 mg/kg, i.v.). Epinephrine (4-128 μg/kg, i.v.) -induced arrhythmias and plasma levels of epinephrine (Epi) and norepinephrine (NE) were determined in control, 4- and 8-wk diabetic animals. Echocardiography was used to assess cardiac remodeling and contractile function. Results: Although diabetes induced cardiac dysfunction, there were no significant differences in cardiac output, ejection fraction, left ventricle (LV) dimensions, LV fractional shortening between the 4- and 8-wk diabetic animals. Th e electrocardiogram of both diabetic groups showed deep S wave as well as changes in T wave and ST segment. In addition, prolongation of the RR interval in the 4- and 8-wk diabetic animals was seen, while prolongation of the QT and PR intervals were only seen in the 8-wk diabetic animals. Th e severity of Epi-induced ventricular arrhythmias, as assessed by arrhythmia score, was significantly lower in the 8-wk diabetic rats, as compared to the 4-wk diabetic animals. Circulating Epi levels were significantly decreased in the 8-wk diabetic rats, whereas NE levels were increased in the 4-wk diabetic rats. Conclusions: Th e sensitivity of the diabetic heart to catecholamine- triggered arrhythmias may be dependent on circulating Epi rather than NE and thus it can be proposed that the increased incidence of sudden cardiac death in diabetics may not be associated with response to catecholamines.

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“…MHCs are contractile proteins and the shift from the adult isoform (MHCα) toward a fetal isoform (MHCβ) is implicated in cardiac dysfunction (33). The decreased expression of SERCA2 is also related to cardiac dysfunction because of dysregulation of Ca 2+ handling in the myoplasm (34). Rivoglitazone had no effects on the expression levels of MHCs and SERCA2.…”

Section: Discussionmentioning

confidence: 99%

Potent Antidiabetic Effects of Rivoglitazone, a Novel Peroxisome Proliferator–Activated Receptor-γ Agonist, in Obese Diabetic Rodent Models

et al. 2009

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Abstract. The pharmacological effects of rivoglitazone, a novel thiazolidinedione-derivative peroxisome proliferator-activated receptor (PPAR)-γ agonist, were characterized in vitro and in vivo. Rivoglitazone activated human PPARγ more potently compared with rosiglitazone and pioglitazone and had little effect on PPARα and PPARδ activity in luciferase reporter assays. In Zucker diabetic fatty (ZDF) rats, 14-day administration of rivoglitazone decreased the plasma glucose and triglyceride (TG) levels in a dose-dependent manner. The glucose-lowering effect of rivoglitazone was much more potent than those of pioglitazone (ED 50 : 0.19 vs. 34 mg/kg) and rosiglitazone (ED 50 : 0.20 vs. 28 mg/kg). In addition, rivoglitazone showed potent antidiabetic effects in diabetic db/db mice. In Zucker fatty rats, rivoglitazone at a dose of 0.1 mg/kg clearly ameliorated insulin resistance and lowered plasma TG levels by accelerating the clearance of plasma TG. Gene expression analysis in the liver and heart of ZDF rats treated with rivoglitazone for 14 days suggested that rivoglitazone may reduce hepatic glucose production and modulate the balance of the cardiac glucose/fatty acid metabolism in diabetic animals. In summary, we showed that rivoglitazone is a potent and selective PPARγ agonist and has a potent glucoselowering effect via improvement of the insulin resistance in diabetic animal models.

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Depressed Levels of Ca2+-Cycling Proteins May Underlie Sarcoplasmic Reticulum Dysfunction in the Diabetic Heart

Cited by 113 publications

References 35 publications

Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation

Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation

Susceptibility of Diabetic Heart to Catecholamine-induced Arrhythmias is Independent of Contractile Dysfunction

Potent Antidiabetic Effects of Rivoglitazone, a Novel Peroxisome Proliferator–Activated Receptor-γ Agonist, in Obese Diabetic Rodent Models

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