Subcellular mechanisms of adaptation in the diabetic myocardium: Relevance to ischemic preconditioning in the nondiseased heart (original) (raw)
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Cardiovascular Research, 1996
Objective: Studies have shown that the diabetic heart exhibits abnormalities in cellular ion transport, which can affect susceptibility to reperfusion-induced ventricular fibrillation (VF), tachycardia (VT) and functional derangements. It has been shown that "preconditioning" renders the heart very resistant to a subsequent prolonged ischemic episode. This phenomenon has been extensively studied in healthy myocardium, but such a study has not been previously done in diseased (hypertrophic or myopathic) hearts. Methods: We studied the incidence of reperfusion-induced VF, VT, cardiac function, and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia/reperfusion in isolated hearts from rats with streptozotocin-induced diabetes. Following 2, 4, 6, and 8 weeks of diabetes, hearts were isolated and subjected to 30 min global ischemia followed by reperfusion. Results: In the 2-week diabetic group the total incidence of VF and VT was reduced from their non-diabetic age-matched control value of 100 and 100% to 42 (P < 0.05) and 42% (P < 0.051, respectively. Such a reduction in the incidence of VF and VT was not observed with progressive diabetes (4, 6, and 8 weeks). In the 2-week diabetics, the reduction in the VF and VT was reflected in the improvement of postischemic function, the reduction of ischemia and reperfusion-induced Na+ and Ca2+ gains, and the prevention in K+ and Mg 2+ loss This diabetes-induced initial protection was not seen in the 4-and . 6-week diabetics, and a deterioration of postischemic function was observed in the 8-week diabetics. Four cycles of preconditioning, each consisting of 5 min ischemia followed by 10 min reperfusion, failed to reduce the incidence of VF and VT, improve cardiac function, and prevent ion shifts induced by 30 min ischemia followed by 30 min reperfusion in 4-and 8-week diabetics. Conclusions: In the early phase of diabetes the heart is pore resistant to ischemia/reperfusion than the non-diabetic heart. Preconditioning does not afford protection against a prolonged period of ischemia in diabetics, indicating that preconditioning may be a "healthy heart phenomenon".
Diabetologia, 2011
Aims/hypothesis Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K ATP channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/ reperfusion (I/R). Methods Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 μmol/l) and gc (1.0 μmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia.
Protection afforded by preconditioning to the diabetic heart against ischaemic injury
Cardiovascular Research, 1998
. Objective: The aim of this study was to assess whether the cardioprotective effect of ischaemic preconditioning IPC on endothelial function in coronary arteries and myocardial function is affected in the streptozotocin-induced diabetic rat heart. Methods: Isolated Ž y1 . hearts, perfused under constant flow conditions, were exposed to 30 min of partial ischaemia flow rate 1 ml min followed by 20 min Ž . Ž . of reperfusion. Results: In the diabetic group without ischaemia or IPC , infusion of 10 mM serotonin 5-HT , an endothelium-depen-Ž . dent, and 3 mM sodium nitroprusside SNP , an endothelium-independent vasodilator, in the coronary bed preconstricted with 0.1 mM U-46619 induced a marked vasodilation. Ischaemia, either without or with preconditioning with a single 5 min ischaemia and 10 min Ž . reperfusion IPC1 before ischaemia, was accompanied by a reduced 5-HT-induced vasodilation in diabetic hearts. In contrast, IPC1 preserved the response to 5-HT in non-diabetic hearts. A more extensive IPC with 3 periods of 5 min ischaemia followed by 5 min Ž . reperfusion IPC3 preserved the vasodilation produced by 5-HT in both diabetic and non-diabetic hearts. IPC3 increased the recovery of d Prdt and d Prdt during the 30 min ischaemic period and during reperfusion in all hearts. In contrast, IPC1 had no effect on max min myocardial recovery in either groups. Adenosine pre-treatment started 30 min before ischaemia mimicked IPC3, preserving the vasodilation to 5-HT and improving myocardium recovery in both groups. When adenosine was started 15 min before ischaemia, vasodilation to 5-HT was preserved in non-diabetic hearts only. Conclusions: These results suggest that IPC affords protection to endothelial function in resistance coronary arteries of diabetic hearts. To achieve this protection, a more extensive IPC is needed, which may be related to a longer exposure to adenosine. q 1998 Elsevier Science B.V.
Diabetologia, 2006
Aims/hypothesis: An important determinant of sensitivity to ischaemia is altered ion homeostasis, especially disturbances in intracellular Na + Na þ i À Á handling. As no study has so far investigated this in type 2 diabetes, we examined susceptibility to ischaemia-reperfusion in isolated hearts from diabetic db/db and control db/+ mice and determined whether and to what extent the amount of Na þ i increase during a transient period of ischaemia could contribute to functional alterations upon reperfusion. Methods: Isovolumic hearts were exposed to 30-min global ischaemia and then reperfused. 23 Na nuclear magnetic resonance (NMR) spectroscopy was used to monitor Na þ i and 31 P NMR spectroscopy to monitor intracellular pH (pH i). Results: A higher duration of ventricular tachycardia and the degeneration of ventricular tachycardia into ventricular fibrillation were observed upon reperfusion in db/db hearts. The recovery of left ventricular developed pressure was reduced. The increase in Na þ i induced by ischaemia was higher in db/db hearts than in control hearts, and the rate of pH i recovery was increased during reperfusion. The inhibition of Na + /H + exchange by cariporide significantly reduced Na þ i gain at the end of ischaemia. This was associated with a lower incidence of ventricular tachycardia in both heart groups, and with an inhibition of the degeneration of ventricular tachycardia into ventricular fibrillation in db/db hearts. Conclusions/ interpretation: These findings strongly support the hypothesis that increased Na þ i plays a causative role in the enhanced sensitivity to ischaemia observed in db/db diabetic hearts.
Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium
Cardiovascular Research, 2006
Objectives: We have shown previously that human diabetic myocardium cannot be preconditioned. Here, we have investigated the basis of this cardioprotective deficit. Methods: Right atrial sections from four patient groups-non-diabetic, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) receiving glibenclamide, and NIDDM receiving metformin-were subjected to one of the following protocols: aerobic control, simulated ischemia/reoxygenation, ischemic preconditioning before ischemia, and pharmacological preconditioning with alpha 1 agonist phenylephrine, adenosine, the mito-K ATP channel opener diazoxide, the protein kinase C (PKC) activator phorbol-12myristate-13-acetate (PMA), or the p38 mitogen-activated protein kinase (p38MAPK) activator anisomycin. Cellular damage was assessed using creatine kinase leakage and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. In mitochondrial preparations from non-diabetic and diabetic myocardium, mitochondrial membrane potential (W m) was assessed using JC-1 dye, and production of reactive oxygen species was determined. Results: Preconditioning with ischemia, phenylephrine, adenosine, or diazoxide failed to protect diabetic myocardium. However, activation of PKC or p38MAPK was still protective. In isolated non-diabetic mitochondria, diazoxide partially depolarized W m , an effect not seen in diabetic mitochondria. Furthermore, diazoxide increased superoxide production in non-diabetic but not in diabetic mitochondria. Conclusions: Our results show that the cardioprotective deficit in diabetic myocardium arises upstream of PKC and p38MAPK. We suggest that mitochondrial dysfunction in diabetic myocardium, possibly dysfunctional mito-K ATP channels, leads to impaired depolarization and superoxide production, and that this causes the inability to respond to preconditioning.
Effects of diabetes and hypertension on myocardial Na<sup>+</sup>-Ca<sup>2+</sup> exchange
Canadian Journal of Physiology and Pharmacology, 2000
Abnormalities in cardiac function have been extensively documented in experimental and clinical diabetes. These aberrations are well known to be exaggerated when hypertension and diabetes co-exist. The objective of the present study was to examine whether alterations in the activity of the myocardial Na +-Ca 2+ exchanger (NCX) can account for the deleterious effects of diabetes and (or) hypertension on the heart. To this aim, the following experimental groups were studied: (i) control; (ii) diabetic; (iii) hypertensive; and (iv) hypertensive-diabetic. Wistar rats served as the control group (C) while Wistar rats injected with streptozotocin (STZ, 55 mg/kg) served as the diabetic (D) group. Spontaneously hypertensive (SH) rats were used as the hypertensive group (H) while SH rats injected with STZ served as the hypertensive-diabetic (HD) group. Sarcolemma was isolated from the ventricles of the C, D, H, and HD groups and NCX activity was examined using rapid quenching techniques to study initial rates over a [Ca 2+ ] o range of 10-160 µM. The V max of NCX was lower in the D group when compared with the C group (D, 2.96 ± 0.26 vs. C, 4.0 ± 0.46 nmol•mgprot-1 •s-1 , P < 0.05), however combined diabetes and hypertension (HD) did not affect the V max of NCX activity (HD, 3.84 ± 0.88 vs. H, 3.59 ± 0.24 nmol•mgprot-1 •s-1 , P > 0.05). However, analysis of the K m values for Ca 2+ indicated that both the D and HD groups exhibited a significantly lower K m when compared with their respective control groups (D, 42 ± 4 vs. C, 56 ± 4 µM, P < 0.05; HD, 33 ± 7 vs. H, 51 ± 8 µM, P < 0.05). Immunoblotting using polyclonal antibodies (against canine cardiac NCX) exhibited the typical banding of 160, 120, and 70 kDa. The 120 kDa band is believed to represent the native exchanger with its post-translational modifications. Examination of the blots revealed a lower intensity of the 120 kDa band in the D group when compared with the C group, however, no significant difference in the HD group was observed. We speculate that the lower V max in the D group may be due to a reduced concentration of exchanger protein in the membrane. The absence of this defect in the HD group may be a result of compensatory mechanisms to the overall hemodynamic overload, however, this remains to be determined. The increased affinity for Ca 2+ in both the D and HD groups (determined by the lower K m values) is an interesting finding and may be due to changes in sarcolemmal lipid bilayer composition secondary to diabetes-induced hyperlipidemia.
Mechanisms that may be involved in calcium tolerance of the diabetic heart
The Cellular Basis of Cardiovascular Function in Health and Disease, 1997
In diabetes the hearts exhibit impaired membrane functions, but also increased tolerance to Ca 2+ (iCaT) However, neither the true meaning nor the molecular mechanisms of these changes are fully understood. The present study is devoted to elucidation of molecular alterations, particularly those induced by non-enzymatic glycation of proteins, that may be responsible for iCaT of the rat hearts in the stage of fully developed, but still compensated diabetic cardiomyopathy (DH). Insulin-dependent diabetes (DIA) was induced by a single i.v. dose of streptozotocin (45 mg.kg -1 ). Beginning with the subsequent day, animals obtained 6 U insulin daily. Glucose, triglycerides, cholesterol and glycohemoglobin were investigated in blood. ATPase activities, the kinetics of activation of (Na,K)-ATPase by Na + and K + , further the fluorescence anisotropy of diphenyl-hexatriene as well as the order parameters of membranes in isolated heart sarcolemma (SL) were also investigated. In addition, the degree of glycation and glycation-related potency for radical generation in SL proteins were determined by investigating their fructosamine content. In order to study calcium tolerance of DH in a 'transparent' model, hearts were subjected to calcium paradox (Ca-Pa, 3 min of Ca 2+ depletion; 10 min of Ca 2+ repletion). In this model of Ca 2+ -overload, Ca 2+ ions enter the cardiac cells in a way that is not mediated by receptors. Results revealed that more than 83% of the isolated perfused DH recovered, while the non-DIA control hearts all failed after Ca-Pa. DH exhibited well preserved SL ATPase activities and kinetics of (Na,K)-ATPase activation by Na + , even after the Ca-Pa. This was considered as a reason for their iCaT. Pretreatment and administration of resorcylidene aminoguanidine (RAG 4 or 8 mg.kg -1 ) during the disease prevented partially the pathobiochemical effects of DIA-induced glycation of SL proteins. DIA-induced perturbations in anisotropy and order parameters of SL were completely prevented by administration of RAG (4 mg.kg -1 ). Although, the latter treatment exerted little influence on the (Na,K)-ATPase activity, it decreased the calcium tolerance of the DH. Results are supporting our hypothesis that the glycation-induced enhancement in free radical formation and protein crosslinking in SL may participate in adaptive mechanisms that may be also considered as 'positive' and are responsible for iCaT of the DH. (Mol Cell Biochem 176: 191-198, 1997)
American Journal of Physiology-Heart and Circulatory Physiology, 2001
Diabetes increases both the incidence of cardiovascular disease and complications of myocardial infarction and heart failure. Studies using diabetic animals have shown that changes in myocardial sodium transporters result in alterations in intracellular sodium (Nai) homeostasis. Because the changes in sodium homeostasis can be due to increased entry of Na+via the electroneutral Na+-K+-2Cl−cotransporter (NKCC), we conducted experiments in acute diabetic hearts to determine if 1) net inward cation flux via NKCC is increased, 2) this cotransporter contributes to a greater increase in Naiduring ischemia, and 3) inhibition of NKCC limits injury and improves function after ischemia-reperfusion. These issues were investigated in perfused type I diabetic and nondiabetic rat hearts subjected to ischemia and 60 min of reperfusion. A group of diabetic and nondiabetic hearts was perfused with 5 μM of bumetanide, an inhibitor of NKCC. Flux via NKCC, Nai, and ATP was measured in each group with t...
Experimental diabetes research, 2012
Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2-6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibitio...