心不全とER ストレス
Mitochondrial Bioenergetics
Many studies have examined mitochondrial bioenergetics either in heart failure or in diabetes. Both conditions are associated with impaired mitochondrial oxidative capacity and oxidative stress. However, diabetes might be more likely to be associated with increased mitochondrial uncoupling, which contributes to impaired cardiac efficiency in the diabetic heart 158. There is considerable evidence linking heart failure with impaired myocardial energetics 137. Reduced cardiac PCr/ATP ratio has been reported in explanted human hearts 159, in 31P MRS studies in humans with HFrEF 160, in patients with HFpEF 161 and in animal models of pressure overload HF 162. Similar changes in myocardial pCr/ATP ratios have been reported in subjects with diabetes with mild diastolic impairment. Impaired mitochondrial respiration and altered mitochondrial ultrastructure have been observed in rodent models of insulin resistance and diabetes and have been previously reviewed 163. Thus, the possibility exists that the superimposition of diabetes and heart failure could further impair mitochondrial bioenergetics. Intriguingly, this specific question has not been widely studied. Although animal studies that have attempted to maintain expression levels of regulators of mitochondrial biogenesis such as PGC1-α have not led to preservation of myocardial function, additional mechanisms linking impaired mitochondrial bioenergetics and heart failure could potentially be targeted therapeutically. These include ROS-mediated mitochondrial uncoupling, a characteristic of diabetic cardiomyopathy that in animal studies could be ameliorated by treatment with anti-oxidants 164, 165. Similar effects have been reported in animal models of heart failure 166, 167, but few studies have examined a role for ROS-scavenging when diabetes and heart failure co-exist. Another molecular target that is emerging as a potential treatment for heart failure are strategies that replete the myocardial pool of NAD+ using for example nicotinamide riboside (NR) 168. Although NR has also been studied in diabetic neuropathy, a role for therapeutic manipulation of this pathway in the context of diabetes and heart failure remains an important question for future studies. Finally, altered E-C coupling represents an important pathophysiological mechanism that is altered both in heart failure and in models of diabetic cardiomyopathy. Calcium re-uptake via SERCA-2 into the SR is an energy-dependent process, which is impaired in heart failure and in models of diabetic cardiomyopathy. For example, cardiomyocytes from ob/ob mice exhibited elevated cytosolic Ca2+, delayed removal of Ca2+ and reduced amplitudes of Ca2+ transients related to reduced SERCA-2a activity and impaired Ca2+ reuptake 169-171. Adenoviral overexpression of SERCA-2 was shown to improve E-C coupling in animal models of type 1 and type 2 diabetes 172.
Lipotoxicity and Glucotoxicity
The systemic metabolic perturbations associated with uncontrolled diabetes presents the myocardium with a surplus of fuels such as fatty acids, ketones and glucose. The inability of the heart to process these substrates stem in part from mitochondrial dysfunction leading to the accumulation of toxic byproducts of these cardiac fuels that may contribute to increased myocardial injury. The net effect of this imbalance between substrate supply and metabolic capacity and the aberrant signaling that ensues from metabolic byproducts of lipid or glucose metabolism has been termed lipotoxicity or glucotoxicity respectively, or when their effects occur in concert, the synergistic pathological consequences have been described as glucolipotoxicity. The topic of myocardial lipotoxicity has been extensively reviewed 173, 174. There is a general consensus that lipotoxicity arises from the increased availability of lipid intermediates such as ceramides, diacylglycerol or oxidized phospholipids 19. Lipotoxic cardiomyopathy has been achieved in many animal models by increasing FA uptake 19. Excess lipid can be stored as triglycerides and are also shunted into non oxidative pathways, disrupting normal cellular signaling and leading to apoptosis and organ dysfunction 173. Metabolites that arise from glycolysis such as sorbitol the product of aldose reductase, the initial step in the polyol pathway has been implicated in promoting oxidative stress. O-GlcNAC modifications of proteins as discussed earlier, resulting from increased flux through the hexosamine biosynthetic pathway has variable consequences which could be cardioprotective or deleterious 175. Recent studies have also revealed that glucose or its metabolites might also impact myocardial gene expression by direct effects on transcription factors or by epigenetic mechanisms 176. Although, in the context of diabetes, adaptations develop in the heart to reduce glucose uptake, persistent hyperinsulinemia, hyperglycemia and increased circulating fatty acids may conspire to limit “protective” adaptations leading to a cumulative impact of toxic byproducts of glucose and lipid metabolism, - “glucolipotoxicity”. From a therapeutic stand-point the most effective approaches to limit glucolipotoxicity will likely be those that limit excessive substrate delivery to the heart and mitigating hyperinsulinemia. As discussed elsewhere in this review, existing glucose lowering therapies address some but not all of these variables and might have independent effects on the myocardium, which depending on the agent may provide additional benefit (e.g. SGLT2 inhibitors) or generate adverse effects (e.g. TZDs). A non-pharmacological approach, namely bariatric surgery which represents a treatment that is most likely to lead to diabetes reversal may come close to addressing many of the metabolic abnormalities that promote glucolipotoxicity and is discussed next.
