Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats

Wold, Loren E.; Dutta, Kaushik; Mason, Meredith M.; Ren, Jun; Cala, Steven E.; Schwanke, Mary L.; Davidoff, Amy J.

doi:10.1016/j.yjmcc.2005.03.014

Cited by 111 publications

(125 citation statements)

References 49 publications

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“…6d-f). Interestingly, approximately the same proportion of myocytes from sucrose-and starch-fed females (∼80%) could be driven to contract at 5 Hz, whereas we have previously reported [11] a striking difference between myocytes from sucrose-and starch-fed males in terms of capability to be paced at 5 Hz (50 vs 84%, respectively). As reported in an earlier study [10], sucrose feeding does not produce uniformly adverse effects on all cardiac myocytes, such that a subset of these heart cells appears to have 'normal' function.…”

Section: +contrasting

confidence: 51%

“…prolonged myocyte shortening and relengthening and slowed cytosolic Ca 2+ removal. As previously discussed [10,11], this model is particularly intriguing in that impaired myocyte mechanics appears prior to overt ventricular dysfunction in the whole heart.…”

Section: Introductionmentioning

confidence: 91%

“…In our sucrose-fed model, we recently demonstrated that sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) function is depressed [11], thus providing one possible mechanism for the ability of isoprenaline to improve relaxation. Here we show that a low concentration of isoprenaline (i.e.…”

Section: +mentioning

confidence: 96%

“…were undertaken based on our previous findings that Ca 2+ regulation is altered in myocytes from sucrose-fed rats [10,11], consistent with a variety of other models of cardiac dysfunction in diabetes (reviewed in [15,16]). Increasing extracellular Ca 2+ has been shown to normalise cardiac function in streptozotocin-induced type 1 diabetic animals [35].…”

Section: +mentioning

confidence: 99%

“…We have tried a CaMKII inhibitor with an in vitro model of high-glucose-induced myocardial dysfunction, and have preliminary evidence that CaMKII is required for the improvement of relaxation by high (4 mmol/l) [Ca 2+ ] o (Dutta and Davidoff, unpublished data). In that model, as in the sucrose-fed model, impaired SERCA function has been demonstrated [11,40]. Whether a sex-related difference in CaMKII level or activity occurs with sucrose feeding remains to be investigated.…”

Section: +mentioning

confidence: 99%

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Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

et al. 2006

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Aims/hypothesis: The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. Materials and methods: Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca 2+ in order to determine whether altered Ca 2+ availability contributes to the cardiomyocyte dysfunction. Results: Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10 −8 mol/l isoprenaline, elevated extracellular Ca 2+ , and higher rates of stimulation). Twice as much extracellular Ca 2+ (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. Conclusions/ interpretation: These data suggest that in myocytes from insulin-resistant rats altered Ca 2+ handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions.

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Section: +contrasting

confidence: 51%

Section: Introductionmentioning

confidence: 91%

Section: +mentioning

confidence: 96%

Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

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Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

et al. 2006

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Involvement of L‐type calcium channel and serca2a in myocardial dysfunction induced by obesity

Leopoldo

Sugizaki

Nascimento

et al. 2011

Journal Cellular Physiology

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Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca(2+) ) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca(2+) channels and sarcoplasmic reticulum (SR) Ca(2+) -ATPase (SERCA2a), may contribute to the cardiac dysfunction induced by obesity. The purpose of this study was to investigate whether myocardial dysfunction in obese rats is related to decreased activity and/or expression of L-type Ca(2+) channels and SERCA2a. Male 30-day-old Wistar rats were fed standard (C) and alternately four palatable high-fat diets (Ob) for 15 weeks. Obesity was determined by adiposity index and comorbidities were evaluated. Myocardial function was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic and lusitropic maneuvers. L-type Ca(2+) channels and SERCA2a activity were determined using specific blockers, while changes in the amount of channels were evaluated by Western blot analysis. Phospholamban (PLB) protein expression and the SERCA2a/PLB ratio were also determined. Compared with C rats, the Ob rats had increased body fat, adiposity index and several comorbidities. The Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca(2+) was compromised. The diltiazem promoted higher inhibition on developed tension in obese rats. In addition, there were no changes in the L-type Ca(2+) channel protein content and SERCA2a behavior (activity and expression). In conclusion, the myocardial dysfunction caused by obesity is related to L-type Ca(2+) channel activity impairment without significant changes in SERCA2a expression and function as well as L-type Ca(2+) protein levels.

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Earlier onset of diabesity‐Induced adverse cardiac remodeling in female compared to male mice

Bowden

Tesch

Julius

et al. 2015

Obesity

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Objective: Emerging evidence suggests female type 2 diabetes (T2DM) patients may fare worse than males with respect to cardiovascular complications. Hence the impact of sex on relative progression of left ventricular (LV) remodeling in obese db/db mice was characterized. Methods: The changes in parameters of LV hypertrophy (heart weight, pro-hypertrophic gene expression, cardiomyocyte size) and fibrosis (LV collagen deposition and oxidative stress), in parallel with body weight and blood glucose and lipid profiles, in male and female db/db T2DM mice, at 10, 14, and 18 weeks of age, were determined. Results: Diabesity-induced cardiac remodeling was at least comparable in female (compared to male) mice. Females exhibited enhanced systemic oxidative stress and nonesterified fatty acid levels. Progression of LV pro-hypertrophic (b-myosin heavy chain, B-type natriuretic peptide) and pro-oxidant gene expression (NADPH oxidase subunit Nox2, plasminogen activator inhibitor-1 PAI-I) was, however, exaggerated in females when expressed relative to 10-week-old db/db mice. Increased cardiomyocyte width was also evident earlier in db/db females than males. No other gender differences were observed. Conclusions: Progressive, age-dependent development of cardiac remodeling in db/db mice parallels impairments in glucose handling and oxidative stress. Certain aspects of the T2DM-induced LV remodeling response may have an earlier and/or exaggerated onset in diabetic females.

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Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats

Cited by 111 publications

References 49 publications

Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

Involvement of L‐type calcium channel and serca2a in myocardial dysfunction induced by obesity

Earlier onset of diabesity‐Induced adverse cardiac remodeling in female compared to male mice

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