Altered myocardial mechanics in diabetic rats.

Fein, F. S.; Kornstein, Laura; Strobeck, John E.; Capasso, J. M.; Sonnenblick, Edmund H.

doi:10.1161/01.res.47.6.922

Cited by 341 publications

(177 citation statements)

References 26 publications

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“…Although STZ-induced diabetes is an established model to generate diabetic cardiomyopathy (7,27), it has not been used to directly quantitate diabetic cardiomyopathy in mice, although it has been used to study the effect of diabetes on skeletal muscle (28). We confirm that STZinduced diabetes in mice leads to a pronounced diabetic cardiomyopathy similar to that observed in larger animals (6,28,29). The contractile parameters were assessed ex vivo in a whole-heart preparation and in strips of isolated papillary muscles.…”

Section: Discussionsupporting

confidence: 66%

Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

et al. 2002

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Diabetic cardiomyopathy is characterized by reduced cardiac contractility due to direct changes in heart muscle function independent of vascular disease. An important contributor to contractile dysfunction in the diabetic state is an impaired sarcoplasmic reticulum (SR) function, leading to disturbed intracellular calcium handling. We investigated whether overexpression of the SR calcium pump (SERCA2a) in transgenic mice could reduce the impact of diabetes on the development of cardiomyopathy. Diabetes was induced by streptozotocin injection (200 mg/kg), and left ventricular (LV) function was analyzed in isolated hearts 3 weeks later. In diabetic hearts systolic LV pressure was decreased by 15% and maximum speed of relaxation (؊dP/dt) by 34%. Functional changes were also assessed in isolated papillary muscles. Active force was reduced by 61% and maximum speed of relaxation by 65% in the diabetic state. The contractile impairment was accompanied by a 30% decrease in SERCA2a protein in diabetic mice. We investigated whether increased SERCA2a expression in transgenic SERCA2a-overexpressing mice could compensate for the diabetes-induced decrease in cardiac function. Under normal conditions, SERCA2a overexpressors show improved contractile performance relative to wild-type (WT) mice (؊dP/dt: 3,169 vs. 2,559 mmHg/s, respectively). Measurement of LV function in hearts from diabetic SERCA2a mice revealed systolic and diastolic functions that were similar to WT control mice and markedly improved relative to diabetic WT mice (؊dP/dt: 2,534 vs. 1,690 mmHg/s in diabetic SERCA2a vs. diabetic WT mice, respectively). Similarly, the contractile behavior of isolated papillary muscles from diabetic SERCA2a mice was not different from that of control mice. SERCA2a protein expression was higher (60%) in diabetic SERCA2a mice than WT diabetic mice. These results indicate that overexpression of SERCA2a can protect diabetic hearts from severe contractile dysfunction, presumably by improving the calcium sequestration of the SR.

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Section: Discussionsupporting

confidence: 66%

Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

et al. 2002

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“…Diabetes is also frequently associated with the development of heart failure, even in the absence of coronary artery complications or hypertension (20). The mechanisms involved in diabetes-induced cardiac problems are not clearly understood, but bradycardia (2,21) and decreased chronotropic and inotropic responses to ␤-AR-agonist stimulation (1-3) have been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

et al. 2001

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Diabetic hearts exhibit decreased responsiveness to stimulation by ␤-adrenoreceptor (␤-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of ␤-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to ␤ 1 -AR agonist stimulation, but not to ␤ 2 -AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that ␤ 1 -AR mRNA and protein levels decreased by 34.9 ± 5.8 and 44.4 ± 5.8%, respectively, in 14 week-STZtreated diabetic rat hearts when compared with agematched controls. On the other hand, mRNA levels encoding ␤ 2 -and ␤ 3 -ARs increased by 72.5 ± 16.6 and 97.3 ± 26.1%, respectively. Although the latter translated into a proportional increase in ␤ 3 -AR protein levels (100.0 ± 17.0%), ␤ 2 -AR protein levels decreased to 82.6 ± 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored ␤ 1 -AR mRNA and protein levels to 60.1 ± 8.4 and 83.2 ± 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding ␤ 2 -and ␤ 3 -ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of ␤-AR agonists may be due to a decrease in ␤ 1 -AR and an increase ␤ 3 -AR expression. Diabetes 50: [455][456][457][458][459][460][461] 2001

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“…4 - 5 Characteristics of abnormal ventricular relaxation in diabetes include increased durations and reduced rates of decline in either the tension of isolated muscle 1 or the pressure of the intact ventricle. 2 -3 One mechanism by which diabetes produces an impairment of ventricular muscle relaxation may involve the rate of calcium sequestration by the sarcoplasmic reticulum (SR).…”

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confidence: 99%

“…In normotensive diabetic rats, insulin therapy can ameliorate impaired mechanical function without completely correcting the depressed serum thyroid hormone levels. 1 The dose of T 3 used in the current study (8-10 ^.g/kg/day) was selected on the basis of its ability to restore the depressed heart rate in vivo of diabetic SHR to normal (see Table 3). This dose probably did not impose a hyperthyroid state in the diabetic SHR for several reasons: 1) It did not significantly increase serum T 3 levels above those of the nondiabetic controls, although it apparently did inhibit T 4 production by the thyroid gland (Table 1); 2) The same dose given to the nondiabetic SHR had no effect on heart or body weights, or on systolic arterial pressure or heart rate in vivo (Tables 2 and 3); 3) T 3 treatment of nondiabetic SHR also had no significant effect on either serum T 3 levels (Table 1), indexes of mechanical relaxation, or the rate of SR Ca 2+ uptake in vitro (Tables 4 and 5).…”

mentioning

confidence: 99%

Ventricular relaxation of diabetic spontaneously hypertensive rat.

1990

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Diabetes, and possibly the hypothyroidism that attends diabetes, impairs mechanical relaxation of ventricular muscle, in part by depressing the rate of Ca 2+ uptake by sarcoplasmic reticulum. Left ventricular hypertrophy exacerbates the adverse effects of diabetes on cardiac performance, but its effects on relaxation variables have not been well characterized. We examined the impact of streptozotocin-induced diabetes (8 weeks) on ventricular pressure load-dependent relaxation and sarcoplasmic reticular calcium uptake of hearts from spontaneously hypertensive rats and Wistar-Kyoto rats. Subsets of diabetic hypertensive rats were treated with either insulin (10 units/kg/day) or triiodothyronine (8-10 /tg/kg/day). Diabetes impaired load-dependent relaxation and depressed sarcoplasmic reticular calcium uptake only in spontaneously hypertensive rat hearts. Either insulin or triiodothyronine treatment prevented the diabetes-induced depressions of both mechanical and biochemical indexes of relaxation. The results suggest that 1) hypertrophic ventricles of spontaneously hypertensive rats are more susceptible to the detrimental effects of diabetes on relaxation indexes than are the nonhypertrophic Wistar-Kyoto rat ventricles, and 2) the hypothyroidism that attends diabetes may contribute to the impaired relaxation of diabetic spontaneously hypertensive rat left ventricle. have an impact on ventricular relaxation. The presence of LVH alone may or may not be associated with impaired relaxation. "17 However, when diabetes coexists with LVH in the spontaneously hypertensive rat (SHR), the rate of left ventricular pressure decline of perfused hearts is more profoundly depressed when compared with the effects of diabetes in normotensive rat strains. -13 Isometric relaxation is also prolonged in hypertrophic papillary muscles from the diabetic renovascular hypertensive rat.12 These results would suggest that combined effects of diabetes and LVH on SR Ca 2+ uptake might be more pronounced than the influence of either condition individually. However, the interaction between diabetes and LVH on the relation between myocardial relaxation and SR calcium uptake has not been characterized.Reduced serum levels of thyroid hormones are often associated with diabetes, l *-n and this hypothyroidism (or "low thyroid state") may contribute to diabetic cardiomyopathy. Thyroid hormone deficiencies, like diabetes, can lead to prolonged relaxation and depressed rates of SR calcium uptake in the myocardium. 18- 19 The effects of hypothyroidism on these measurements are well correlated, both in nonhypertrophic and hypertrophic ventricles. 20 Treatment of the diabetic SHR with triiodothyronine (T 3 ) effectively prevents the resultant cardiac dysfunction, 21 -22 but the influence of T 3 treatment in nonhypertensive diabetic rat models is inconsistent.

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Altered myocardial mechanics in diabetic rats.

Cited by 341 publications

References 26 publications

Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

Ventricular relaxation of diabetic spontaneously hypertensive rat.

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