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Cells Oct 2022Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this...
AIMS
Krüppel-like Factor 9 (KLF9) is a transcription factor that regulates multiple disease processes. Studies have focused on the role of KLF9 in the redox system. In this study, we aimed to explore the effect of KLF9 on diabetic cardiomyopathy.
METHODS AND RESULTS
Cardiac-specific overexpression or silencing of KLF9 in C57BL/6 J mice was induced with an adeno-associated virus 9 (AAV9) delivery system. Mice were also subjected to streptozotocin injection to establish a diabetic cardiomyopathy model. In addition, neonatal rat cardiomyocytes were used to assess the possible role of KLF9 in vitro by incubation with KLF9 adenovirus or small interfering RNA against KLF9. To clarify the involvement of peroxisome proliferator-activated receptors (PPARγ), mice were subjected to GW9662 injection to inhibit PPARγ. KLF9 was upregulated in the hearts of mice with diabetic cardiomyopathy and in cardiomyocytes. In addition, KLF9 overexpression in the heart deteriorated cardiac function and aggravated hypertrophic fibrosis, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. Conversely, cardiac-specific silencing of KLF9 ameliorated cardiac dysfunction and alleviated hypertrophy, fibrosis, the cardiac inflammatory response and oxidative stress. In vitro, KLF9 silencing in cardiomyocytes enhanced inflammatory cytokine release and oxidative stress; KLF9 overexpression increased these detrimental responses. Moreover, KLF9 was found to regulate the transcription of PPARγ, which suppressed the expression and nuclear translocation of nuclear Factor E2-related Factor 2 (NRF2). In mice injected with a PPARγ inhibitor, the protective effects of KLF9 knockdown on diabetic cardiomyopathy were counteracted by GW9662 injection.
CONCLUSIONS
KLF9 aggravates cardiac dysfunction, the inflammatory response and oxidative stress in mice with diabetic cardiomyopathy. KLF9 may become a therapeutic target for diabetic cardiomyopathy.
Topics: Animals; Mice; Rats; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Kruppel-Like Transcription Factors; Mice, Inbred C57BL; NF-E2-Related Factor 2; PPAR gamma; Streptozocin
PubMed: 36359788
DOI: 10.3390/cells11213393 -
Cells Nov 2021Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and... (Review)
Review
Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.
Topics: Animals; Diabetic Cardiomyopathies; Fatty Acids; Humans; Models, Biological; Myocardium; Oxidation-Reduction; Severity of Illness Index
PubMed: 34831481
DOI: 10.3390/cells10113259 -
Biochimica Et Biophysica Acta.... May 2018
Topics: Adaptation, Physiological; Animals; Congresses as Topic; Diabetes Mellitus; Diabetic Cardiomyopathies; Energy Metabolism; Heart; Heart Diseases; Humans; Insulin Resistance; Myocardium; Obesity; Risk Factors
PubMed: 29391209
DOI: 10.1016/j.bbadis.2018.01.024 -
Cardiovascular Diabetology Jan 2024Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel)...
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.
Topics: Humans; Mice; Rats; Animals; Diabetic Cardiomyopathies; Myocytes, Cardiac; Vascular Endothelial Growth Factor B; Melatonin; Endoplasmic Reticulum Chaperone BiP; Diabetes Mellitus, Experimental; Signal Transduction; Autophagy; Glucose
PubMed: 38195474
DOI: 10.1186/s12933-023-02078-x -
Diabetes Feb 2022Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over...
Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects. When administered in normal animals, both the recombinant human wild-type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protected the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic db/db mice, rhMG53-WT treatment markedly aggravated hyperglycemia, cardiac I/R injury, and mortality, whereas acute and chronic treatment with rhMG53-C14A still effectively ameliorated I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without metabolic adverse effects. Furthermore, knock-in of MG53-C14A protected the mice from high-fat diet-induced metabolic disorders and cardiac damage. Thus, the E3 ligase-dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteracts metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injury in metabolic disorders, including diabetes and obesity.
Topics: Animals; Cells, Cultured; Cytoprotection; Diabetic Cardiomyopathies; Diet, High-Fat; Female; Heart; Humans; Male; Membrane Proteins; Metabolic Syndrome; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Signal Transduction
PubMed: 34844991
DOI: 10.2337/db21-0322 -
Gaceta Medica de Mexico 2023Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity;...
Diabetic cardiomyopathy (DCM) is a serious complication of diabetes caused by oxidative stress, inflammation, insulin resistance, myocardial fibrosis, and lipotoxicity; its nature is insidious, complex and difficult to treat. NLRP3 inflammasome triggers the maturation and release of pro-inflammatory cytokines, participates in pathophysiological processes such as insulin resistance and myocardial fibrosis, in addition to being closely related to the development and progression of diabetic cardiomyopathy. The development of inhibitors targeting specific aspects of inflammation suggests that NLRP3 inflammasome can be used to treat diabetic cardiomyopathy. This paper aims to summarize NLRP3 inflammasome mechanism and therapeutic targets in diabetic cardiomyopathy, and to provide new suggestions for the treatment of this disease.
Topics: Animals; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Diabetic Cardiomyopathies; Insulin Resistance; Diabetes Mellitus, Experimental; Inflammation; Fibrosis
PubMed: 37494725
DOI: 10.24875/GMM.22000403 -
Frontiers in Endocrinology 2021
Topics: Cardiovascular Diseases; Ceramides; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Humans
PubMed: 33776946
DOI: 10.3389/fendo.2021.667885 -
Implications of Underlying Mechanisms for the Recognition and Management of Diabetic Cardiomyopathy.Journal of the American College of... Jan 2018Heart failure is a complex clinical syndrome, the incidence and prevalence of which is increased in diabetes mellitus, pre-diabetes, and obesity. Although this may arise... (Review)
Review
Heart failure is a complex clinical syndrome, the incidence and prevalence of which is increased in diabetes mellitus, pre-diabetes, and obesity. Although this may arise from underlying coronary artery disease, it often occurs in the absence of significant major epicardial coronary disease, and most commonly manifests as heart failure with preserved ejection fraction. Despite epidemiological evidence linking diabetes to heart failure incidence and outcome, the presence of a distinct primary "diabetic" cardiomyopathy has been difficult to prove, because the link between diabetes and heart failure is confounded by hypertension, microvascular dysfunction, and autonomic neuropathy. Nonetheless, several mechanistic associations at systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. This review seeks to describe recent advances and limitations pertinent to integrating molecular mechanisms, clinical screening, and potential therapeutic avenues for this condition.
Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Management; Heart Failure; Humans
PubMed: 29348027
DOI: 10.1016/j.jacc.2017.11.019 -
Endocrine Reviews Apr 2017Chronic, low-grade systemic inflammation and impaired microvascular function are critical hallmarks in the development of insulin resistance. Accordingly, insulin... (Review)
Review
Chronic, low-grade systemic inflammation and impaired microvascular function are critical hallmarks in the development of insulin resistance. Accordingly, insulin resistance is a major risk factor for type 2 diabetes and cardiovascular disease. Accumulating studies demonstrate that restoration of impaired function of the diabetic macro- and microvasculature may ameliorate a range of cardiovascular disease states and diabetes-associated complications. In this review, we focus on the emerging role of microRNAs (miRNAs), noncoding RNAs that fine-tune target gene expression and signaling pathways, in insulin-responsive tissues and cell types important for maintaining optimal vascular homeostasis and preventing the sequelae of diabetes-induced end organ injury. We highlight current pathophysiological paradigms of miRNAs and their targets involved in regulating the diabetic microvasculature in a range of diabetes-associated complications such as retinopathy, nephropathy, wound healing, and myocardial injury. We provide an update of the potential use of circulating miRNAs diagnostically in type I or type II diabetes. Finally, we discuss emerging delivery platforms for manipulating miRNA expression or function as the next frontier in therapeutic intervention to improve diabetes-associated microvascular dysfunction and its attendant clinical consequences.
Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Diabetic Nephropathies; Humans; MicroRNAs
PubMed: 28323921
DOI: 10.1210/er.2016-1122 -
International Journal of Molecular... Dec 2016Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism.... (Review)
Review
Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on "differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury".
Topics: Animals; Diabetic Cardiomyopathies; Extracellular Signal-Regulated MAP Kinases; Histone Deacetylase Inhibitors; Humans; MAP Kinase Signaling System; MicroRNAs; Phosphorylation
PubMed: 27941647
DOI: 10.3390/ijms17122001