Secreted frizzled-related protein 2 ameliorates diabetic cardiomyopathy by activating mitophagy.

OBJECTIVES: Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in metabolic disorders. However, its effect on diabetic cardiomyopathy was still unclear. Accumulating evidence indicates that mitophagy can protect cardiac function in the diabetic heart. The present study aimed to explore the roles of SFRP2 on diabetic cardiomyopathy, focusing on the effects and mechanisms for regulating mitophagy. METHODS: Wild-type H9c2 cells, Sfrp2 overexpression and knockdown H9c2 cells were exposed to a glucolipotoxic milieu. Reactive oxygen species (ROS) production, cell viability, apoptosis, mitophagy and lysosomal activity were detected. The interaction of SFRP2 with frizzled 5 (FZD5), and its effect on expression and intracellular localization of transcription factor EB (TFEB) and ß-catenin were also explored. Diabetic rats and Sfrp2 overexpression diabetic rats were constructed to further document the findings from the in vitro study. RESULTS: The expression of SFRP2 was low and mitophagy was inhibited in H9c2 cells in a glucolipotoxic milieu. Sfrp2 overexpression activated mitophagy and reduced H9c2 cells injury, whereas Sfrp2 deficiency inhibited mitophagy and worsened this injury. Consistent with the in vitro findings, Sfrp2 overexpression ameliorated the impairment in cardiac function of diabetic rats by activating mitophagy. Sfrp2 overexpression upregulated the expression of calcineurin and TFEB, but did not affect ß-catenin in vitro and in vivo. The calcineurin inhibitor tacrolimus can inhibit mitophagy and worsen cell injury in Sfrp2 overexpression H9c2 cells. Furthermore, we found that FZD5 is required for the SFRP2-induced activation of the calcineurin/TFEB pathway and interacts with SFRP2 in H9c2 cells. Transfection with small interfering RNA targeting FZD5 opposed the effects of Sfrp2 overexpression on mitophagy and cell survival in a glucolipotoxic environment. CONCLUSIONS: SFRP2 can protect the diabetic heart by interacting with FZD5 and activating the calcineurin/TFEB pathway to upregulate mitophagy in H9c2 cells.

Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.

With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD.

Association between the ratio of serum eicosapentaenoic acid to arachidonic acid and risk of coronary artery disease in young Chinese patients.

Objective: Long-chain (LC) omega-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may play an anti-inflammatory effect and decrease the risk of coronary artery disease (CAD). In contrast, omega-6 PUFA, mainly arachidonic acid (AA), has pro-inflammatory and pro-aggregatory effects, which may increase the risk of CAD. This study evaluated the associations between EPA, DHA, AA, and their ratios (EPA/AA and DHA/AA) with the risk of CAD in young Chinese patients. Methods: A total of 182 young patients with CAD and 143 age-matched controls were included. Traditional cardiovascular risk factors were recorded. Serum EPA, DHA and AA were measured by ultra-performance liquid chromatography-mass spectrometry. Results: The level of AA was significantly higher, while the level of EPA was lower in the CAD group than that in the control group. There was no significant difference in DHA level in the two groups. Both the ratios of EPA/AA and DHA/AA were lower in the CAD group than that in the control. Multivariate logistic regression analysis showed that higher serum AA level was associated with the increased risk of CAD, while EPA was a protective factor for CAD. There was no significant association between DHA level and the risk of CAD. Although both higher ratios of EPA/AA [per tertile increment, adjusted odds ratios (ORs) (OR) 0.356, 95% confidence intervals (CI) 0.247-0.513] and DHA/AA (adjusted OR = 0.465, 95%CI = 0.332-0.653) were associated with a lower risk of CAD in young patients. Receiver operating characteristic (ROC) curve analysis showed that compared with AA, the diagnostic value was increased in EPA/AA, but not in DHA/AA. Conclusion: EPA, but not DHA may play a protective role in CAD, while AA may be associated with the increased risk of CAD in young Chinese patients. The ratio of EPA/AA can increase the predictive value for diagnosing CAD than EPA or AA alone.

Association between non-alcoholic fatty liver disease and risk of incident heart failure: a meta-analysis of observational studies.

Background and aims: Recent research has associated non-alcoholic fatty liver disease (NAFLD) with an increased risk of atherosclerotic cardiovascular disease. Previous studies that evaluated the association between NAFLD and risk of heart failure (HF) yielded inconsistent results, however. This meta-analysis aimed to evaluate the association between NAFLD and the risk of HF. Methods: We searched multiple electronic databases, including PubMed, Google Scholar, Embase and Web of Science for potential studies published from inception until 30 October 2021. Cohort studies reported multivariable-adjusted risks of incident HF in NAFLD patients comparing those without NAFLD were included. Results: Six cohort studies comprising 10,979,967 participants (women = 55.5%) were included in the study. The median prevalence of NAFLD in these studies was 22.2%. During a median follow-up duration of 7.0 years, 92,915 HF cases were detected. In the unadjusted model, patients with NAFLD had a greater risk of incident HF [random-effect hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.25-1.75, I 2 = 99%], compared with those without NAFLD. After multivariable adjustment of confounding risk factors, NAFLD was still linked with a higher risk of HF incidence (random-effect HR = 1.36, 95% CI = 1.16-1.58, I 2 = 98%). The risk of HF was increased not only in patients with progressive NAFLD severity but also in those with simple steatosis. The absolute risk difference of HF in NAFLD patients compared with those without NAFLD was 11.0 (95% CI = 4.9-17.7) per 10,000 person-years after multivariable adjustment. Conclusion: This meta-analysis suggests that NAFLD may be associated with an increased risk of incident HF. Owing to the high heterogeneity of the published studies, however, further high-quality studies are still needed.

Association of NAFLD with cardiovascular disease and all-cause mortality: a large-scale prospective cohort study based on UK Biobank.

Objective: Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, sharing the similar cardiometabolic risk factors with cardiovascular disease (CVD). Whether NAFLD by itself is associated with increased cardiovascular events and death remain an issue to debate. This study aimed to further investigate the association between NAFLD and adverse CVD outcomes. Methods: Participants were followed up until the end of 2020 in current analysis. NAFLD is defined using fatty liver index (FLI). Cox proportional hazard model was used to analyze the association between NAFLD and all-cause mortality, major adverse cardiovascular events (MACEs), CVD mortality, fatal/nonfatal acute myocardial infarction (AMI), and fatal/nonfatal stroke. C-index was calculated to evaluate the model enhancement when adding NAFLD factor. Results: After screening the data of 502,492 participants in the original cohort, 215,245 eligible participants were included in this study for MACEs outcome. Compared with non-NAFLD participants, the multivariable adjusted hazard ratios of NAFLD group was 1.25 (1.14-1.36) for MACEs; 1.14 (1.08-1.20) for all-cause mortality; 1.61(1.42-1.82) for CVD mortality; 1.58(1.19-2.11) for AMI mortality; and 1.18 (0.85-1.64) for stroke mortality. When adding FLI, C-index of NAFLD model improved for all-cause mortality, MACEs, and CVD mortality compared with that in the traditional CVD risk factor model. Conclusion: NAFLD is an independent risk factor for all-cause mortality and adverse CVD outcomes. Based on the traditional CVD risk factor model, additionally screening NAFLD could improve the prediction efficiency for adverse CVD outcomes.

Association between prediabetes and adverse outcomes in heart failure.

AIMS: Patients with heart failure (HF) and with diabetes experienced significantly worse outcomes than those without diabetes. However, data on the prognostic impact of prediabetes in HF are inconclusive. This meta-analysis aimed to explore the association between prediabetes and the risk of all-cause mortality and adverse cardiac outcomes in patients with HF. MATERIALS AND METHODS: We searched multiple electronic databases (PubMed, Embase and Google Scholar) for relevant studies up to 31 March 2021. Studies were included for analysis if multivariable adjusted relative risks of adverse outcomes were reported in patients with prediabetes and with HF compared with those with normoglycaemia. Random-effects models were used to calculate the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Twelve studies comprising 28 643 patients with HF reported the risk of all-cause mortality and cardiac outcomes associated with prediabetes. The prevalence of prediabetes ranged from 9.6% to 37.2%. After a median follow-up duration of 2.3 years, patients with HF and with prediabetes were associated with an increased risk of all-cause mortality (HR 1.29, 95% CI 1.06-1.58), cardiovascular mortality (HR 1.59, 95% CI 1.09-2.32), HF hospitalization (HR 1.33, 95% CI 1.09-1.61), all-cause mortality and/or HF hospitalization (HR 1.22, 95% CI 1.01-1.47), as well as cardiovascular mortality and/or HF hospitalization (HR 1.21, 95% CI 1.07-1.37). CONCLUSIONS: Prediabetes is associated with a worse prognosis in patients with HF. Further risk stratification and effective treatment strategies are needed in patients with prediabetes and with HF to improve the prognosis.