CaMKII Inhibition is a Novel Therapeutic Strategy to Prevent Diabetic Cardiomyopathy

Increasing prevalence of diabetes mellitus worldwide has pushed the complex disease state to the foreground of biomedical research, especially concerning its multifaceted impacts on the cardiovascular system. Current therapies for diabetic cardiomyopathy have had a positive impact, but with diabetic patients still suffering from a significantly greater burden of cardiac pathology compared to the general population, the need for novel therapeutic approaches is great. A new therapeutic target, calcium/calmodulin-dependent kinase II (CaMKII), has emerged as a potential treatment option for preventing cardiac dysfunction in the setting of diabetes. Within the last 10 years, new evidence has emerged describing the pathophysiological consequences of CaMKII activation in the diabetic heart, the mechanisms that underlie persistent CaMKII activation, and the protective effects of CaMKII inhibition to prevent diabetic cardiomyopathy. This review will examine recent evidence tying cardiac dysfunction in diabetes to CaMKII activation. It will then discuss the current understanding of the mechanisms by which CaMKII activity is enhanced during diabetes. Finally, it will examine the benefits of CaMKII inhibition to treat diabetic cardiomyopathy, including contractile dysfunction, heart failure with preserved ejection fraction, and arrhythmogenesis. We intend this review to serve as a critical examination of CaMKII inhibition as a therapeutic strategy, including potential drawbacks of this approach.

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Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

10.21203/rs.3.rs-33214/v1 ◽

2020 ◽

Author(s):

Jinxin Wang ◽

Jing Bai ◽

Peng Duan ◽

Hao Wang ◽

Yang Li ◽

...

Keyword(s):

Cardiac Function ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Diabetic Patients ◽

Protein Levels ◽

Inwardly Rectifying Potassium Channel ◽

Transmission Electron ◽

Hematoxylin And Eosin ◽

And Function

Abstract Background: Diabetic cardiomyopathy (DCM) severely impairs the health of diabetic patients. Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 DCM have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM.Methods: The cardiac function in mice was analyzed by echocardiography, ELISA, hematoxylin and eosin staining, TUNEL and transmission electron microscopy. The mitochondrial function in cardiomyocytes was measured by the oxygen consumption rate and the mitochondrial membrane potential (ΔΨm). Kir6.1 expression at the mRNA and protein levels was analyzed by quantitative real-time PCR and western blotting (WB), respectively. The protein expression of t-AKT, p-AKT, t-Foxo1, and p-Foxo1 was analyzed by WB.Results: We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. Kir6.1 overexpression improved cardiac dysfunction and upregulated the phosphorylation of AKT and Foxo1 in the DCM mouse model. Furthermore, Kir6.1 overexpression also improved cardiomyocyte dysfunction and upregulated the phosphorylation of AKT and Foxo1 in cardiomyocytes with insulin resistance. In contrast, cardiac-specific Kir6.1 knockout aggravated the cardiac dysfunction and downregulated the phosphorylation of AKT and Foxo1 in DCM mice. Furthermore, Foxo1 activation downregulated the expression of Kir6.1 and decreased the ΔΨm in cardiomyocytes. In contrast, Foxo1 inactivation upregulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional Foxo1-binding site .Conclusions: Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-Foxo1 signaling pathway. Moreover, the crosstalk between Kir6.1 and the AKT-Foxo1 signaling pathway may provide new strategies for reversing the defective signaling in DCM.

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Investigation of the Protective Effects of Phlorizin on Diabetic Cardiomyopathy indb/dbMice by Quantitative Proteomics

Journal of Diabetes Research ◽

10.1155/2013/263845 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

Qian Cai ◽

Baoying Li ◽

Fei Yu ◽

Weida Lu ◽

Zhen Zhang ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Body Weight Gain ◽

Fasting Blood Glucose ◽

Interaction Network ◽

Diabetic Patients ◽

Protective Effects ◽

Absolute Quantitation ◽

Patients With Diabetes ◽

Itraq Proteomics ◽

Isobaric Tag

Patients with diabetes often develop hypertension and atherosclerosis leading to cardiovascular disease. However, some diabetic patients develop heart failure without hypertension and coronary artery disease, a process termed diabetic cardiomyopathy. Phlorizin has been reported to be effective as an antioxidant in treating diabetes mellitus, but little is known about its cardioprotective effects on diabetic cardiomyopathy. In this study, we investigated the role of phlorizin in preventing diabetic cardiomyopathy indb/dbmice. We found that phlorizin significantly decreased body weight gain and the levels of serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and advanced glycation end products (AGEs). Morphologic observations showed that normal myocardial structure was better preserved after phlorizin treatment. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics, we identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function, and cardiomyopathy, suggesting that phlorizin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. We used ingenuity pathway analysis (IPA) to generate an interaction network to map the pathways containing these proteins. Our findings provide important information about the mechanism of diabetic cardiomyopathy and also suggest that phlorizin may be a novel therapeutic approach for the treatment of diabetic cardiomyopathy.

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Abstract 16563: FOXO1 Induces Cardiomyocyte-KLF5, Which Drives Oxidative Stress and Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.16563 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ioannis D Kyriazis ◽

Matthew K Hoffman ◽

Lea Gaignebet ◽

Anna Maria Lucchese ◽

Chao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Constitutive Expression ◽

Diabetic Patients ◽

Mrna Levels ◽

Dependent Manner ◽

Lipid Species ◽

Ceramide Accumulation ◽

Klf5 Expression

Introduction: Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice. Hypothesis: KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM). Methods and Results: Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC- Foxo1 -/- mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ), which we generated, recapitulated cardiomyopathy without T1D. Moreover, Pparα -/- mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA- Klf5 mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA- Klf5 with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity. Conclusions: In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.

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Regulation of Sirtuin-Mediated Protein Deacetylation by Cardioprotective Phytochemicals

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1750306 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 29

Author(s):

Niria Treviño-Saldaña ◽

Gerardo García-Rivas

Keyword(s):

Heart Failure ◽

Cardiovascular Diseases ◽

Posttranslational Modifications ◽

Cardiac Dysfunction ◽

Therapeutic Strategy ◽

Alpha Lipoic Acid ◽

Protein Acetylation ◽

Cardioprotective Effects ◽

Expression And Activity ◽

Novel Therapeutic

Modulation of posttranslational modifications (PTMs), such as protein acetylation, is considered a novel therapeutic strategy to combat the development and progression of cardiovascular diseases. Protein hyperacetylation is associated with the development of numerous cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. In addition, decreased expression and activity of the deacetylases Sirt1, Sirt3, and Sirt6 have been linked to the development and progression of cardiac dysfunction. Several phytochemicals exert cardioprotective effects by regulating protein acetylation levels. These effects are mainly exerted via activation of Sirt1 and Sirt3 and inhibition of acetyltransferases. Numerous studies support a cardioprotective role for sirtuin activators (e.g., resveratrol), as well as other emerging modulators of protein acetylation, including curcumin, honokiol, oroxilyn A, quercetin, epigallocatechin-3-gallate, bakuchiol, tyrosol, and berberine. Studies also point to a cardioprotective role for various nonaromatic molecules, such as docosahexaenoic acid, alpha-lipoic acid, sulforaphane, and caffeic acid ethanolamide. Here, we review the vast evidence from the bench to the clinical setting for the potential cardioprotective roles of various phytochemicals in the modulation of sirtuin-mediated deacetylation.

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RIPK3-Mediated Necroptosis in Diabetic Cardiomyopathy Requires CaMKII Activation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6617816 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Yun Chen ◽

Xinshuai Li ◽

Yuyun Hua ◽

Yue Ding ◽

Guoliang Meng ◽

...

Keyword(s):

Protein Kinase ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Myocardial Injury ◽

Recombinant Adenovirus ◽

Gene Knockout ◽

Kinase Domain ◽

Receptor Interaction ◽

Dependent Manner ◽

Camkii Activation

Activation of Ca2+/calmodulin-dependent protein kinase (CaMKII) has been proved to play a vital role in cardiovascular diseases. Receptor-interaction protein kinase 3- (RIPK3-) mediated necroptosis has crucially participated in cardiac dysfunction. The study is aimed at investigating the effect as well as the mechanism of CaMKII activation and necroptosis on diabetic cardiomyopathy (DCM). Wild-type (WT) and the RIPK3 gene knockout (RIPK3-/-) mice were intraperitoneally injected with 60 mg/kg/d streptozotocin (STZ) for 5 consecutive days. After 12 w of feeding, 100 μL recombinant adenovirus solution carrying inhibitor 1 of protein phosphatase 1 (I1PP1) gene was injected into the caudal vein of mice. Echocardiography, myocardial injury, CaMKII activity, necroptosis, RIPK1 expression, mixed lineage kinase domain-like protein (MLKL) phosphorylation, and mitochondrial ultrastructure were measured. The results showed that cardiac dysfunction, CaMKII activation, and necroptosis were aggravated in streptozotocin- (STZ-) stimulated mice, as well as in (Lepr) KO/KO (db/db) mice. RIPK3 deficiency alleviated cardiac dysfunction, CaMKII activation, and necroptosis in DCM. Furthermore, I1PP1 overexpression reversed cardiac dysfunction, myocardial injury and necroptosis augment, and CaMKII activity enhancement in WT mice with DCM but not in RIPK3-/- mice with DCM. The present study demonstrated that CaMKII activation and necroptosis augment in DCM via a RIPK3-dependent manner, which may provide therapeutic strategies for DCM.

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GDF11 alleviates pathological myocardial remodeling in diabetic cardiomyopathy through SIRT1-dependent regulation of oxidative stress and apoptosis

10.21203/rs.3.rs-357210/v1 ◽

2021 ◽

Author(s):

Hanzhao Zhu ◽

Liyun Zhang ◽

Mengen Zhai ◽

Lin Xia ◽

Yu Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Sirtuin 1 ◽

H9c2 Cell ◽

Diabetic Patients ◽

Intramyocardial Injection

Abstract Background Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte injury, which induced by metabolic disorder. Nowadays, there is still a lack of drugs for the treatment of DCM. Growth differentiation factor 11 (GDF11) is a novel member of the transforming growth factor β superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in DCM remain largely unknown. Methods In this study, we sought to determine whether GDF11 could prevent DCM. The mouse model of diabetes was established by administering a high-fat diet and intraperitoneal injecting streptozotocin. After that, intramyocardial injection of an adeno-associated virus carrying GDF11 gene was used to achieve myocardium-specific overexpression. Results Our data showed that GDF11 overexpression remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression was observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were also eliminated by SIRT1 depletion. Conclusion Our results demonstrated for the first time that GDF11 protected against DCM by regulating SIRT1 signaling pathway, and GDF11 had the potential to become a novel target for reversing cardiac dysfunction in diabetic patients.

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IL-12 and IL-23/Th17 axis in systemic lupus erythematosus

Experimental Biology and Medicine ◽

10.1177/1535370218824547 ◽

2019 ◽

Vol 244 (1) ◽

pp. 42-51 ◽

Cited By ~ 14

Author(s):

Maddalena Larosa ◽

Margherita Zen ◽

Mariele Gatto ◽

Diogo Jesus ◽

Elisabetta Zanatta ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Monoclonal Antibody ◽

Lupus Erythematosus ◽

Cell Activation ◽

Therapeutic Strategy ◽

Complex Disease ◽

Controlled Trial ◽

Special Focus ◽

Systemic Lupus ◽

Novel Therapeutic

Systemic lupus erythematosus (SLE) is a very complex disease where multiple immunological pathways can concur in inducing tissue damage. Cytokines are key mediators in this process and among them the role of interleukin (IL)-12 and the IL-23/Th17 axis has recently emerged. IL-12 and IL-23 have a heterodimeric structure with a common subunit, named p40. Although they share a partially common structure, their functions appear slightly different. Indeed, IL-12 is a key cytokine in inducing an efficient T helper 1 (Th1) response and in Th differentiation, while IL-23 plays a crucial role in chronic inflammation and Th17 cell activation, which results in IL-17 secretion. The increasing knowledge on the interaction between IL-12 and IL-23/Th17 axis in the development of autoimmune diseases has led to the identification of new therapeutic strategies targeting these immunological pathways. IL-23/Th17 axis has recently been suggested to be essential in developing lupus nephritis, both in mice and in humans. In keeping with these observations, ustekinumab, a fully human IgG1κ monoclonal antibody (mAb) directed towards p40 subunit, has been investigated in SLE. Promising data from a phase II randomized controlled trial in SLE patients suggest that this mAb might be a potential novel therapeutic strategy in SLE. In this review, we summarize the complex interaction between IL-12 and IL-23/Th17 axis in SLE with a special focus on drugs which affect this immune pathway. Impact statement Our article is focused on emerging pathogenetic pathways in systemic lupus erythematosus (SLE). Notably, IL-12 and IL-23 have been described as emerging cytokines in SLE pathogenesis. We know that IL-23 stimulates Th17 cells to produce IL-17. We try to point out the importance of IL-23/Th17 axis in SLE and to focus on the interaction between this axis and IL-12. Ustekinumab, a fully human IgG1κ monoclonal antibody directed towards the p40 shared subunit of IL-12 and IL-23, has been recently investigated in SLE, suggesting a potential novel therapeutic strategy in SLE. To our knowledge, there are no reviews which simultaneously focus on IL-12 an IL-23/Th17 axis in SLE. Thus, we believe our work will be of interest to the readers.

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The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities

International Journal of Molecular Sciences ◽

10.3390/ijms22115973 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5973

Author(s):

Petra Grubić Rotkvić ◽

Zrinka Planinić ◽

Ana-Marija Liberati Pršo ◽

Jozica Šikić ◽

Edvard Galić ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Clinical Importance ◽

Specific Form ◽

Therapeutic Interventions ◽

Cardiomyocyte Hypertrophy ◽

Diabetic Patients ◽

Therapeutic Guideline ◽

Underlying Mechanisms ◽

Therapeutic Possibilities ◽

Novel Therapeutic

Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.

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Anti-OX40ligand treatment as a novel therapeutic strategy in a murine model of colitis

Gastroenterology ◽

10.1016/s0016-5085(01)83410-7 ◽

2001 ◽

Vol 120 (5) ◽

pp. A685-A685

Author(s):

B SINGH ◽

V MALMSTROM ◽

F POWRIE

Keyword(s):

Murine Model ◽

Therapeutic Strategy ◽

Novel Therapeutic

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Anticancer Immunotoxins, Challenges, and Approaches

Current Pharmaceutical Design ◽

10.2174/1381612826666201006155346 ◽

2020 ◽

Vol 26 ◽

Author(s):

Maryam Dashtiahangar ◽

Leila Rahbarnia ◽

Safar Farajnia ◽

Arash Salmaninejad ◽

Arezoo Gowhari Shabgah ◽

...

Keyword(s):

Therapeutic Strategy ◽

Antibody Fragment ◽

Clinical Use ◽

Multiple Cancer ◽

Main Obstacle ◽

Cancer Types ◽

Recombinant Immunotoxins ◽

Cancerous Cells ◽

High Immunogenicity ◽

Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

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