Query: diabetic cardiomyopathy

title: Mitophagy Is Essential for Maintaining Cardiac Function During High Fat Diet Induced Diabetic Cardiomyopathy
abstract: Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, and intracellular lipid accumulation, termed lipotoxicity. Diabetic hearts utilize fatty acids as a major energy source, which produces high levels of oxidative stress, thereby inducing mitochondrial dysfunction.  To elucidate how mitochondrial function is regulated in diabetic cardiomyopathy.  Mice were fed either a normal diet or high fat diet (HFD, 60 kcal fat) Although autophagic flux was activated by HFD consumption, peaking at 6 weeks (P<0.05) it was attenuated thereafter. Mitophagy, evaluated with Mito Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with normal diet and 12.4% with HFD) and continued to increase even after 2 months (P<0.05) By isolating adult cardiomyocytes from GFP LC3 mice fed HFD, we confirmed that mitochondria were sequestrated by LC3 positive autophagosomes during mitophagy. In wild type mice, cardiac hypertrophy, diastolic dysfunction (end diastolic pressure volume relationship =0.051+ 0.009 in normal diet and 0.11+ 0.004 in HFD) and lipid accumulation occurred within 2 months of HFD feeding (P<0.05) Deletion of atg7 impaired mitophagy, increased lipid accumulation, exacerbated diastolic dysfunction (end diastolic pressure volume relationship =0.11+ 0.004 in wild type and 0.152+ 0.019 in atg7 cKO; P<0.05) and induced systolic dysfunction (end systolic pressure volume relationship =24.86+ 2.46 in wild type and 15.93+ 1.76 in atg7 cKO; P<0.05) during HFD feeding. Deletion of Parkin partially inhibited mitophagy, increased lipid accumulation and exacerbated diastolic dysfunction (end diastolic pressure volume relationship =0.124+ 0.005 in wild type and 0.176+ 0.018 in Parkin KO, P<0.05) in response to HFD feeding. Injection of TB1 (Tat Beclin1) activated mitophagy, attenuated mitochondrial dysfunction, decreased lipid accumulation, and protected against cardiac diastolic dysfunction (end diastolic pressure volume relationship =0.110+ 0.009 in Control peptide and 0.078+ 0.015 in TB1, P<0.05) during HFD feeding.  Mitophagy serves as an essential quality control mechanism for mitochondria in the heart during HFD consumption. Impairment of mitophagy induces mitochondrial dysfunction and lipid accumulation, thereby exacerbating diabetic cardiomyopathy. Conversely, activation of mitophagy protects against HFD induced diabetic cardiomyopathy.

title: Diabetic cardiomyopathy A comprehensive updated review.
abstract: Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called "Diabetic Cardiomyopathy" (DCM) is becoming a well known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.

title: Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy
abstract: Hyperglycemia mediated oxidative damage has been described as a major mechanism leading to pathologic changes associated with diabetic cardiomyopathy (DCM) Fisetin is a bioactive flavonol molecule found in many plants and possesses various biological activities. The present study investigated the protective effect of fisetin on diabetes induced cardiac injury.  Diabetes was induced by streptozotocin (STZ) and both diabetic and control rats were treated with 2.5 mg/kg fisetin for six weeks.  Diabetic rats exhibited hyperglycemia, and increased glycosylated hemoglobin and serum lipids accompanied with significant hypoinsulinism. In addition, diabetic rats showed several histological alterations in the myocardium, and significantly increased serum troponin I, creatine kinase MB and lactate dehydrogenase. Oxidative stress, inflammation and apoptosis markers were increased, whereas antioxidant defenses were significantly reduced in the diabetic heart. Treatment with fisetin alleviated hyperglycemia, hyperlipidemia and heart function markers, and minimized histological alterations in the myocardium. Fisetin suppressed oxidative stress, prevented inflammation and apoptosis, and boosted antioxidant defenses in the heart of diabetic rats.  Fisetin attenuated the development of DCM via amelioration of hyperglycemia/hyperlipidemia mediated oxidative stress, inflammation and apoptosis. Therefore, it might be worth considering the therapeutic potential of fisetin for human DCM. HighlightsFisetin ameliorates hyperglycemia and dyslipidemia in diabetic rats.Fisetin prevents hyperglycemia induced cardiomyopathy in rats.Fisetin attenuates oxidative stress, inflammation and apoptosis in the diabetic heart.

title: Mst1 inhibits Sirt3 expression and contributes to diabetic cardiomyopathy through inhibiting Parkin dependent mitophagy.
abstract: Mitochondrial dysfunction contributes to heart failure induced mortality in approximately 80% of diabetic patients. Mitophagy degrades defective mitochondria and maintains a healthy mitochondrial population, which is essential for cardiomyocyte survival in diabetic stress. Herein, we determined whether Mst1 regulated mitophagy and investigated the downstream signaling pathway in the development of diabetic cardiomyopathy (DCM) Mst1 deficiency promoted elimination of dysfunctional mitochondria in diabetic cardiomyopathy without affecting mitochondrial biogenesis. Enhanced mitophagy was observed in Mst1 interfering cardiomyocytes subjected to high glucose treatment using 3 Methyladenine and Chloroquine. Consistent with these results, in vivo and in vitro loss of function experiments indicated that Mst1 participated in the development of DCM by inhibiting Parkin dependent mitophagy. Mst1 deficiency alleviated the detrimental phenotype of DCM. Interestingly, the protective effects of Mst1 knockout on DCM were compromised in diabetic Parkin mice. Mechanistically, Mst1 knockdown significantly enhanced Parkin expression and translocation to the mitochondria, as evidenced by immunofluorescence study and Western blot analysis. Furthermore, Sirt3 deletion abolished the detrimental effects of Mst1 on DCM. Collectively, Mst1 inhibits Sirt3 expression thus participates in the development of DCM by inhibiting cardiomyocyte mitophagy. The mechanism is associated with Parkin inhibition.

title: Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy
abstract: LCZ696, a first generation dual angiotensin receptor neprilysin inhibitor (ARNi) is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB) and thiorphan [neprilysin inhibitor (NEPi) in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s)  Diabetes was induced by administration of streptozotocin (55 mg/kg, i.p. in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o. or telmisartan (10 mg/kg/day, p.o. monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased PSR positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF kB/MCP 1) profibrotic (TGF b/Smad7) and apoptotic (PARP/Caspase 3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations.  The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.

title: Diabetic cardiomyopathy: prevalence, determinants and potential treatments
abstract: The prevalence of type 2 diabetes (T2D) has reached a pandemic scale. These patients are at a substantially elevated risk of developing cardiovascular disease, with heart failure (HF) being a leading cause of morbidity and mortality. Even in the absence of traditional risk factors, diabetes still confers up to a twofold increased risk of developing HF. This has led to identifying diabetes as an independent risk factor for HF and recognition of the distinct clinical entity, diabetic cardiomyopathy. Despite a wealth of research interest, the prevalence and determinants of diabetic cardiomyopathy remain uncertain. This limited understanding of the pathophysiology of diabetic heart disease has also hindered development of effective treatments. Tight blood glucose and blood pressure control have not convincingly been shown to reduce macrovascular outcomes in T2D. There is, however, emerging evidence that T2D is reversible and that the metabolic abnormalities can be reversed with weight loss. Increased aerobic exercise capacity is associated with significantly lower cardiovascular and overall mortality in diabetes. Whether such lifestyle modifications as weight loss and exercise may ameliorate the structural and functional derangements of the diabetic heart has yet to be established. In this review, the link between T2D and myocardial dysfunction is explored. Insights into the structural and functional perturbations that typify the diabetic heart are first described. This is followed by an examination of the pathophysiological mechanisms that contribute to the development of cardiovascular disease in T2D. Lastly, the current and emerging therapeutic strategies to prevent or ameliorate cardiac dysfunction in T2D are evaluated.

title: Diabetic Cardiomyopathy: Definition, Diagnosis, and Therapeutic Implications.
abstract: A strict bidirectional relationship exists between diabetes mellitus and heart failure. Diabetic cardiomyopathy is a specific cardiac manifestation of patients with diabetes characterized by left ventricular hypertrophy and diastolic dysfunction in the early phase up to overt heart failure with reduced systolic function in the advanced stages. The pathogenesis of this condition is multifactorial and recognizes as main promoting factors the presence of insulin resistance and hyperglycemia. Diabetic cardiomyopathy exerts a negative prognostic impact in affected patients and no target treatments are currently available. More efforts are needed to better define the diagnostic and therapeutic approach in this specific setting.

title: Diabetic Cardiomyopathy: What Is It and Can It Be Fixed?

title: Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity
abstract: Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin angiotensin aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP activated protein kinase, peroxisome proliferator activated receptors, O linked N acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.

title: Non coding RNA involvement in the pathogenesis of diabetic cardiomyopathy
abstract: In recent years, the incidence of diabetes has been increasing rapidly, which seriously endangers human health. Diabetic cardiomyopathy, an important cardiovascular complication of diabetes, is characterized by myocardial fibrosis, ventricular remodelling and cardiac dysfunction. It has been documented that mitochondrial dysfunction, oxidative stress, inflammatory response, autophagy, apoptosis, diabetic microangiopathy and myocardial fibrosis are implicated in the pathogenesis of diabetic cardiomyopathy. With the development of molecular biology technology, accumulating evidence demonstrates that non coding RNAs (ncRNAs) are critically involved in the molecular mechanisms of diabetic cardiomyopathy. In this review, we summarize the pathological roles of three types of ncRNAs (microRNA, long ncRNA and circular RNA) in the progression of diabetic cardiomyopathy, which may provide valuable insights into the pathogenesis of diabetic cardiovascular complications.