Diabetes Mellitus Induces Changes in Cardiac Myosin of the Rat

Abstract

SUMMARYDecreased contractility has been reported in the diabetic heart. Because a close correlation exists between contractility and the activity of Ca 2+ ATPase of purified actinomyosin and myosin, Ca 2+ ATPase activity was determined in control and diabetic rats. In control rats, actinomyosin ATPase was 0.59 ± 0.05 /xmol Pi/mg protein/min and had decreased by 35% to 0.38 ± 0.04 in diabetic rats (P < 0.025). Myosin ATPase activity was 1.25 ± 0.09 /xmol Pi/mg protein/min in control rats and had decreased by 45% to 0.67 ± 0.05 in diabetic animals (P < 0.01). To investigate the decrease in myosin ATPase activity further, ventricular myosin was separated by pyrophosphate polyacrylamide electrophoresis into its three authentic components, V,, V 2 , and V 3 myosin. V 1 has the highest mobility and Ca 2 ATPase activity (1.27 ± 0.3 arbitrary units) and represents 72% of control myosin, whereas V 3 has the lowest mobility and Ca 2+ ATPase activity (0.16 ± 0.08 units) and constitutes 13% of myosin. A marked change in the predominance of V, and V 3 myosin components occurs in diabetic rats where V 3 myosin predominates, representing 68% of total myosin with V 1 myosin constituting only 15%. Ca 2+ ATPase activities of V,, V 2 , and V 3 myosin in control and diabetic hearts are similar; however, the predominance of V 3 myosin in diabetic rats can account for the decreased Ca 2+ ATPase activity of diabetic myosin. The diabetes-induced changes in myosin ATPase activity and myosin isoenzyme distribution can be reverted to control levels by insulin administration. Decreased cardiac contractility in diabetic animals seems quite well established. 5 ' 6 The pathophysiologic mechanisms that underlie the decreased contractility are currently unclear. In particular, it is unknown if changes in the state of contractile proteins contribute to the decreased contractility of the diabetic heart. The activity of Ca 2+ -activated ATPase of actinomyosin and myosin has not been determined in diabetic hearts. A close correlation between the activity of Ca 2+ -activated ATPase of actinomyosin or myosin and cardiac contractility has been well established.7 Furthermore, recent reports have described the occurrence of cardiac myosin isoenzymes.8 -10 These myosin isoenzymes can be separated by electrophoretic techniques into three components that differ in Ca 2+ ATPase activity.The following studies were undertaken to assess the activity of Ca 2+ATPase of actinomyosin and myosin arid to determine if changes in the distribution of myosin isoenzymes occur in diabetic rat hearts. MATERIALS AND METHODSMale Sprague-Dawley rats between 6 and 8 wk of age were used for all experiments. Control and diabetic animals were age-and litter-matched. Rats were made diabetic by i.v. administration of 65 mg streptozotoc in/kg body wt and maintained in a diabetic state for 4 wk. After being diabetic for 4 wk, rats were injected s.c. with 2 U protamine zinc insulin (PSI)/day for 4 wk.11 To assure that animals were diabetic, blood sugars were determined 4 days and 4 wk...

Hypersensitivity to methoxamine in atria isolated from streptozotocin‐induced diabetic rats

“…These findings suggest that under normal conditions, prostacyclin appears to be responsible for the positive inotropic action of Met, while in the diabetic state, thromboxanes could be mediating this effect. In previous studies from our laboratory, positive inotropic actions of prostacyclin (PGI2) and thromboxane B2 (TXB2) in rat isolated atria have been found (Sterin-Borda et al, 1979;1980;1981). Results obtained from radioconversion of labelled arachidonic acid by normal atria confirmed that 6-oxo- prostaglandin Flm (6-oxo-PGF,,,; the non-enzymatic metabolite of PGI2) was the product of AA metabolism generated in preference to TXB2.…”

“…Ramanadham et al (1984) reported not only increased sensitivity of tail artery strips but also a decreased response to a-agonists in thoracic aorta isolated from diabetic rats. However, alterations in cardiac function can develop without coronary vascular complications (Penpargkul et al, 1980;Dillmann, 1980;Vadlamudi et al, 1982). Recently, attention has been focused on the changes which occur in isolated myocardium from rats with chemically-induced diabetes of short duration.…”

Role of resistin in cardiac contractility and hypertrophy

“…Our data suggest that the increased levels of resistin observed in diabetic subjects (rodents as well as humans) may contribute to the development of cardiac hypertrophy which is generally associated with diabetes. Diabetic animals present with characteristic phenotypic abnormalities of their heart muscle that result in part from a recapitulation of the fetal gene expression (e.g., ANF, α-skeletal actin and myosin isozyme shifts, with higher β-MHC and lower α-MHC, [24], [25]) similar to what is observed in pressure-overload and heart failure models. These genetic changes lead to myocardial dysfunction in diabetic animal models, resulting in cardiac hypertrophy.…”

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

“…This suggests that SERCA2a overexpression provides sufficient contractile reserve to ameliorate the detrimental effects of diabetes on cardiac contractility. Some of the decrease in contractility in SERCA2a diabetic mice may be caused by additional subcellular changes, like the diabetes-induced switch in myosin isoforms, which leads to a predominant expression of a slower myosin isoform (30,31). Metabolic changes in the diabetic heart, including a lesser uptake of glucose in the absence of insulin or an enhanced dependence on free fatty acids, could also affect cardiac activities.…”