Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Role of arachidonic acid in ischemic heart disease under different comorbidities: risk or protection?

In a translational study involving animal models and human subjects, Lv et al. demonstrate that arachidonic acid (AA) exhibits cardioprotective effects in diabetic myocardial ischemia, suggesting a departure from its known role in promoting ferroptosis-a form of cell death characterized by iron-dependent lipid peroxidation. However, the study does not address how underlying diabetic conditions might influence the metabolic pathways of AA, which are critical for fully understanding its impact on heart disease. Diabetes can significantly alter lipid metabolism, which in turn might affect the enzymatic processes involved in AA's metabolism, leading to different outcomes in the disease process. Further examination of the role of diabetes in modulating AA's effects could enhance the understanding of its protective mechanism in ischemic conditions. This could also lead to more targeted and effective therapeutic strategies for managing myocardial ischemia in diabetic patients, such as optimizing AA levels to prevent heart damage while avoiding exacerbating factors like ferroptosis.

Quercetin Ameliorates Myocardial Injury in Diabetic Rats by Regulating Autophagy and Apoptosis through AMPK/mTOR Signaling Pathway.

A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Cardioprotective effects of curcumin against Diabetic Cardiomyopathies: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: As a common complication of diabetes, diabetic cardiomyopathy (DCM) often leads to further damage to the heart muscle. Curcumin has been proven to have a variety of cardioprotective effects, however, the protective effect against DCM has not been systematically reviewed. PURPOSE: In this study, we aimed to analyze the preclinical (animal model) evidence of curcumin's therapeutic effects in DCM. METHODS: Eight databases and two registry systems were searched from the time of library construction to 1 November 2023. We performed rigorous data extraction and quality assessment. The included studies' methodological quality was appraised using the SYRCLE RoB tool, statistical analyses were carried out using RevMan 5.4 software, and Funnel plots and Egger's test were performed using Stata 17.0 software to assess publication bias. RESULTS: This study included 32 trials with a total of 681 animals. Meta-analysis showed that curcumin significantly improved cardiac function indices (LVEF, LVFS, and LVSd) (p < 0.01), decreased markers of myocardial injury, HW/BW ratio, and randomized blood glucose compared to the control group, in addition to showing beneficial effects on mechanistic indices of myocardial oxidation, inflammation, apoptosis, and autophagy (p < 0.05). CONCLUSIONS: Curcumin may exert cardioprotective effects in DCM through its antioxidant, anti-inflammatory, autophagy-enhancing, and anti-apoptotic effects. Its protective effect is proportional to the dose, and the efficacy may be further increased at a concentration of more than 200 mg/kg, and further validation is needed.

Naringin: Cardioprotective properties and safety profile in diabetes treatment.

Flavonoids derived from plants offer a broad spectrum of therapeutic potential for addressing metabolic syndrome, particularly diabetes mellitus (DM), a prevalent non-communicable disease. Hyperglycemia in DM is a known risk factor for cardiovascular diseases (CVDs), which substantially impact global mortality rates. This review examines the potential effects of naringin, a citrus flavonoid, on both DM and its associated cardiovascular complications, including conditions like diabetic cardiomyopathy. The safety profile of naringin is summarized based on various pre-clinical studies. The data for this review was gathered from diverse electronic databases, including Medline, PubMed, ScienceDirect, SpringerLink, Google Scholar, and Emerald Insight. Multiple pre-clinical studies have demonstrated that naringin exerts hypoglycemic and cardioprotective effects by targeting various vascular mechanisms. Specifically, research indicates that naringin down-regulates the renin-angiotensin and oxidative stress systems while concurrently upregulating ß-cell and immune system functions. Clinical trial outcomes also support the therapeutic potential of naringin in managing hyperglycemic states and associated cardiovascular issues. Moreover, toxicity studies have confirmed the safety of naringin in animal models, suggesting its potential for safe administration in humans. In conclusion, naringin emerges as a promising natural candidate for both antidiabetic and cardioprotective purposes, offering potential improvements in health outcomes. While naringin presents a new avenue for therapies targeting DM and CVDs, additional controlled and long-term clinical trials are necessary to validate its efficacy and safety for human use.

Tectorigenin protects against cardiac fibrosis in diabetic mice heart via activating the adiponectin receptor 1-mediated AMPK pathway.

Diabetic cardiomyopathy (DCM) is a common severe complication of diabetes that occurs independently of hypertension, coronary artery disease, and valvular cardiomyopathy, eventually leading to heart failure. Previous studies have reported that Tectorigenin (TEC) possesses extensive anti-inflammatory and anti-oxidative stress properties. In this present study, the impact of TEC on diabetic cardiomyopathy was examined. The model of DCM in mice was established with the combination of a high-fat diet and STZ treatment. Remarkably, TEC treatment significantly attenuated cardiac fibrosis and improved cardiac dysfunction. Concurrently, TEC was also found to mitigate hyperglycemia and hyperlipidemia in the DCM mouse. At the molecular level, TEC is involved in the activation of AMPK, both in vitro and in vivo, by enhancing its phosphorylation. This is achieved through the regulation of endothelial-mesenchymal transition via the AMPK/TGFß/Smad3 pathway. Furthermore, it was demonstrated that the level of ubiquitination of the adiponectin receptor 1 (AdipoR1) protein is associated with TEC-mediated improvement of cardiac dysfunction in DCM mice. Notably the substantial reduction of myocardial fibrosis. In conclusion, TEC improves cardiac fibrosis in DCM mice by modulating the AdipoR1/AMPK signaling pathway. These findings suggest that TEC could be an effective therapeutic agent for the treatment of diabetic cardiomyopathy.

Protective role of hydrogen sulfide against diabetic cardiomyopathy by inhibiting pyroptosis and myocardial fibrosis.

Diabetic cardiomyopathy (DCM) contributes significantly to the heightened mortality rate observed among diabetic patients, with myocardial fibrosis (MF) being a pivotal element in the disease's progression. Hydrogen sulfide (H2S) has been shown to mitigate MF, but the specific underlying mechanisms have yet to be thoroughly understood. A connection has been established between the evolution of DCM and the incidence of cardiomyocyte pyroptosis. Our research offers insights into H2S protective impact and its probable mode of action against DCM, analyzed through the lens of MF. In this study, a diabetic rat model was developed using intraperitoneal injections of streptozotocin (STZ), and hyperglycemia-stimulated cardiomyocytes were employed to replicate the cellular environment of DCM. There was a marked decline in the expression of cystathionine γ-lyase (CSE), a catalyst for H2S synthesis, in both the STZ-induced diabetic rats and hyperglycemia-stimulated cardiomyocytes. Experimental results in vivo indicated that H2S ameliorates MF and enhances cardiac functionality in diabetic rats by mitigating cardiomyocyte pyroptosis. In vitro assessments highlighted the induction of cardiomyocyte pyroptosis and the subsequent decline in cell viability under hyperglycemic conditions. However, the administration of sodium hydrosulfide (NaHS) curtailed cardiomyocyte pyroptosis and augmented cell viability. In contrast, propargylglycine (PAG), a CSE inhibitor, reversed the effects rendered by NaHS administration. Additional exploration indicated that the mitigating effect of H2S on cardiomyocyte pyroptosis is modulated through the ROS/NLRP3 pathway. In essence, our findings corroborate the potential of H2S in alleviating MF in diabetic subjects. This therapeutic effect is likely attributable to the regulation of cardiomyocyte pyroptosis via the ROS/NLRP3 pathway. This discovery furnishes a prospective therapeutic target for the amelioration and management of MF associated with diabetes.

Cholesterol 25-hydroxylase prevents type 2 diabetes mellitus induced cardiomyopathy by alleviating cardiac lipotoxicity.

OBJECTIVES: Diabetic cardiomyopathy (DCM) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients, with its underlying mechanisms still elusive. This study aims to investigate the role of cholesterol-25-monooxygenase (CH25H) in T2DM induced cardiomyopathy. METHODS: High fat diet combined with streptozotocin (HFD/STZ) were used to establish a T2DM model. CH25H and its product 25-hydroxycholesterol (25HC) were detected in the hearts of T2DM model. Gain- or loss-of-function of CH25H were performed by receiving AAV9-cTNT-CH25H or CH25H knockout (CH25H-/-) mice with HFD/STZ treatment. Cardiac function was evaluated using echocardiography, and cardiac tissues were collected for immunoblot analysis, histological assessment and quantitative polymerase chain reaction (qPCR). Mitochondrial morphology and function were evaluated using transmission electron microscopy (TEM) and Seahorse XF Cell Mito Stress Test Kit. RNA-sequence analysis was performed to determine the molecular changes associated with CH25H deletion. RESULTS: CH25H and 25HC were significantly decreased in the hearts of T2DM mice. CH25H-/- mice treated with HFD/STZ exhibited impaired mitochondrial function and structure, increased lipid accumulation, and aggregated cardiac dysfunction. Conversely, T2DM mice receiving AAV9-CH25H displayed cardioprotective effects. Mechanistically, RNA sequencing and qPCR analysis revealed that CH25H deficiency decreased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target gene expression. Additionally, administration of ZLN005, a potent PGC-1α activator, partially protected against high glucose and palmitic acid induced mitochondria dysfunction and lipid accumulation in vitro. CONCLUSION: Our study provides compelling evidence supporting the protective role of CH25H in T2DM-induced cardiomyopathy. Furthermore, the regulation of PGC-1α may be intricately involved in this cardioprotective process.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart.

Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Here, we investigated in a cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Compared to wild-type mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC-1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK-3ß/HK-Ⅱ activity via AMPK mediated p70S6K inhibition.

Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1ß pathway in juvenile rats.

Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1ß pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1ß (IL1ß). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway.

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

Diallyl trisulfide (DATS) protects cardiac cells against advanced glycation end-product-induced apoptosis by enhancing FoxO3A-dependent upregulation of miRNA-210.

Diabetic cardiomyopathy is a common complication of diabetes, resulting in cardiac hypertrophy and heart failure associated with excessive reactive oxygen species and mitochondria-mediated apoptosis generation. Mitogen-activated protein kinase-c-Jun N-terminal kinase (MAPK-JNK), regulated by microRNA (miR)-210, affects mitochondrial function and is activated by advanced glycation end-products (AGE) in cardiac cells. Diallyl trisulfide (DATS), an antioxidant in garlic oil, inhibits stress-induced cardiac apoptosis. This study examined whether DATS enhances miR-210 expression to attenuate cardiac apoptosis. We investigated the DATS-mediated attenuation mechanism of AGE-enhanced cardiac apoptosis by modulating miR-210 and its upstream transcriptional regulator, FoxO3a. We found FoxO3a binding sites in the miR-210 promoter region. Our results indicated that DATS treatment inhibited AGE-induced JNK activation, phosphoprotein c-Jun nuclear transactivation, and cardiac apoptosis and reversed the AGE-induced reduction in cardiac miR-210 levels. The luciferase activity after DATS treatment was significantly lower than that of the control and was reversed following AGE treatment. We also showed that FoxO3a, upregulated by DATS treatment, may bind to the miR-210 promoter to enhance its expression and downregulates JNK expression to attenuate AGE-induced cardiac apoptosis. Oral administration of DATS enhanced FoxO3a expression in the heart and reduced diabetes-induced heart apoptosis. Our findings indicate that DATS mediates AGE-induced cardiac cell apoptosis attenuation by promoting FoxO3a nuclear transactivation to enhance miR-210 expression and regulate JNK activation. Our results suggest that DATS can be used as a cardioprotective agent, and miR-210 is a critical regulator in inhibiting diabetic cardiomyopathy.

Beyond the beat: A pioneering investigation into exercise modalities for alleviating diabetic cardiomyopathy and enhancing cardiac health.

Patients with preexisting cardiovascular disease or those at high risk for developing the condition are often offered exercise as a form of therapy. Patients with cancer who are at an increased risk for cardiovascular issues are increasingly encouraged to participate in exercise-based, interdisciplinary programs due to the positive correlation between these interventions and clinical outcomes following myocardial infarction. Diabetic cardiomyopathy (DC) is a cardiac disorder that arises due to disruptions in the homeostasis of individuals with diabetes. One of the primary reasons for mortality in individuals with diabetes is the presence of cardiac structural damage and functional abnormalities, which are the primary pathological features of DC. The aetiology of dilated cardiomyopathy is multifaceted and encompasses a range of processes, including metabolic abnormalities, impaired mitochondrial function, dysregulation of calcium ion homeostasis, excessive cardiomyocyte death, and fibrosis. In recent years, many empirical investigations have demonstrated that exercise training substantially impacts the prevention and management of diabetes. Exercise has been found to positively impact the recovery of diabetes and improve several metabolic problem characteristics associated with DC. One potential benefit of exercise is its ability to increase systolic activity, which can enhance cardiometabolic and facilitate the repair of structural damage to the heart caused by DC, leading to a direct improvement in cardiac health. In contrast, exercise has the potential to indirectly mitigate the pathological progression of DC through its ability to decrease circulating levels of sugar and fat while concurrently enhancing insulin sensitivity. A more comprehensive understanding of the molecular mechanism via exercise facilitates the restoration of DC disease must be understood. Our goal in this review was to provide helpful information and clues for developing new therapeutic techniques for motion alleviation DC by examining the molecular mechanisms involved.

Role of the integrin-linked kinase/TGF-ß/SMAD pathway in sitagliptin-mediated cardioprotective effects in a rat model of diabetic cardiomyopathy.

OBJECTIVES: Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-ß signaling via the SMAD and integrin-linked kinase (ILK) pathways. METHODS: Four groups of male Wistar albino rats were used, with six rats in each group. Two nondiabetic and two diabetic (produced by a single intraperitoneal dose of streptozotocin (55 mg/kg)) groups were administered either normal saline or sitagliptin (100 mg/kg) orally for 6 weeks. Subsequently, HW/BW ratios and cardiac enzymes were assessed, along with a histological examination of cardiac tissues. Levels of TGF-ß, collagen I, p-SMAD2/3, TNF-α, MMP-9, and ILK were detected. RESULTS: Compared with the diabetic control group, sitagliptin-treated diabetic rats exhibited considerably reduced HW/BW ratios and troponin I and creatine kinase-MB levels, with improvements in histopathological changes in cardiac tissues. TGF-ß, collagen I, p-SMAD2/3, TNF-α, and MMP-9 levels were significantly decreased in the sitagliptin-treated diabetic group, whereas ILK was elevated following sitagliptin treatment. CONCLUSION: Sitagliptin could afford cardioprotective effects for the first time by altering ILK-associated TGF-ß/SMAD signaling pathways. Thus, sitagliptin may be a promising therapeutic target for the prevention of diabetic cardiomyopathy.

Cardioprotective effects of asiaticoside against diabetic cardiomyopathy: Activation of the AMPK/Nrf2 pathway.

Diabetic cardiomyopathy (DCM) is a chronic microvascular complication of diabetes that is generally defined as ventricular dysfunction occurring in patients with diabetes and unrelated to known causes. Several mechanisms have been proposed to contribute to the occurrence and persistence of DCM, in which oxidative stress and autophagy play a non-negligible role. Diabetic cardiomyopathy is involved in a variety of physiological and pathological processes. The 5' adenosine monophosphate-activated protein kinase/nuclear factor-erythroid 2-related factor 2 (AMPK/Nrf2) are expressed in the heart, and studies have shown that asiaticoside (ASI) and activated AMPK/Nrf2 have a protective effect on the myocardium. However, the roles of ASI and AMPK/Nrf2 in DCM are unknown. The intraperitoneal injection of streptozotocin (STZ) and high-fat feed were used to establish the DCM models in 100 C57/BL mice. Asiaticoside and inhibitors of AMPK/Nrf2 were used for intervention. Cardiac function, oxidative stress, and autophagy were measured in mice. DCM mice displayed increased levels of oxidative stress while autophagy levels declined. In addition, AMPK/Nrf2 was activated in DCM mice with ASI intervention. Further, we discovered that AMPK/Nrf2 inhibition blocked the protective effect of ASI by compound C and treatment with ML-385. The present study demonstrates that ASI exerts a protective effect against DCM via the potential activation of the AMPK/Nrf2 pathway. Asiaticoside is a potential therapeutic target for DCM.

Inhibition of a novel Dickkopf-1-LDL receptor-related proteins 5 and 6 axis prevents diabetic cardiomyopathy in mice.

BACKGROUND AND AIMS: Anti-hypertensive agents are one of the most frequently used drugs worldwide. However, no blood pressure-lowering strategy is superior to placebo with respect to survival in diabetic hypertensive patients. Previous findings show that Wnt co-receptors LDL receptor-related proteins 5 and 6 (LRP5/6) can directly bind to several G protein-coupled receptors (GPCRs). Because angiotensin II type 1 receptor (AT1R) is the most important GPCR in regulating hypertension, this study examines the possible mechanistic association between LRP5/6 and their binding protein Dickkopf-1 (DKK1) and activation of the AT1R and further hypothesizes that the LRP5/6-GPCR interaction may affect hypertension and potentiate cardiac impairment in the setting of diabetes. METHODS: The roles of serum DKK1 and DKK1-LRP5/6 signalling in diabetic injuries were investigated in human and diabetic mice. RESULTS: Blood pressure up-regulation positively correlated with serum DKK1 elevations in humans. Notably, LRP5/6 physically and functionally interacted with AT1R. The loss of membrane LRP5/6 caused by injection of a recombinant DKK1 protein or conditional LRP5/6 deletions resulted in AT1R activation and hypertension, as well as ß-arrestin1 activation and cardiac impairment, possibly because of multiple GPCR alterations. Importantly, unlike commonly used anti-hypertensive agents, administration of the anti-DKK1 neutralizing antibody effectively prevented diabetic cardiac impairment in mice. CONCLUSIONS: These findings establish a novel DKK1-LRP5/6-GPCR pathway in inducing diabetic injuries and may resolve the long-standing conundrum as to why elevated blood DKK1 has deleterious effects. Thus, monitoring and therapeutic elimination of blood DKK1 may be a promising strategy to attenuate diabetic injuries.

Ginsenoside Rg3 Protects against Diabetic Cardiomyopathy and Promotes Adiponectin Signaling via Activation of PPAR-γ.

Ginsenoside Rg3 extracted from Panax notoginseng has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy (DCM) remains unclear. 24-week-old diabetic db/db mice were treated with ginsenoside Rg3 for 12 weeks, then body weight, serum lipids, adiponectin levels, as well as cardiac function and pathological morphology, were measured. The targets of ginsenoside Rg3 and its regulation of the adiponectin pathway were also evaluated on 3T3-L1 or H9c2 cells. Ginsenoside Rg3 directly bound to PPAR-γ, improving adiponectin secretion and promoting adiponectin signaling. Significantly attenuated overweight, hyperglycemia, and hyperlipidemia, as well as alleviated lipid accumulation and dysfunction in adipose, liver, and heart tissues, were observed in the ginsenoside Rg3-treated group. Ginsenoside Rg3 could be a promising drug targeting PPAR-γ to treat diabetic cardiomyopathy.