bims-hafaim 2022-04-17 papers

Issue of 2022–04–17
seven papers selected by
Kyle McCommis, Saint Louis University

Diabetes Res Clin Pract. 2022 Apr 09. pii: S0168-8227(22)00684-2. [Epub ahead of print] 109871

Benefit of Sodium-Glucose Cotransporter-2 Inhibitors on Survival Outcome is Related to the Type of Heart Failure: A Meta-analysis.

Lingyue Zhao, Wenqin Guo, Weichao Huang, Lili Wang, Siquan Huang.

AIMS: This meta-analysis aimed to evaluate the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in different types of heart failure (HF).
METHODS: Randomized controlled trials (RCTs) comparing SGLT-2 inhibitors with placebo in patients with HF were searched in PubMed, the Cochrane Library database, and clinicaltrials.gov. A random-effects model was used for evidence synthesis. The primary endpoint was cardiac death.
RESULTS: We included 13 studies (12 RCTs). In patients with HF with preserved ejection fraction (HFpEF), SGLT-2 inhibitors reduced the composite endpoint of cardiac death or rehospitalization because of HF (HHF) (HR: 0.78, 95% CI: 0.70-0.87, I2=0%, P<0.001) and that of HHF (HR: 0.74; 95% CI: 0.64-0.85, I2=0%, P<0.001) but not that of cardiac death (HR: 1.01, 95% CI: 0.80-1.28, I2=23.9%, P=0.943). In patients with HF with reduced EF (HFrEF), SGLT-2 inhibitors reduced the composite endpoint of cardiac death or HHF (HR: 0.75, 95% CI: 0.69-0.82, I2=0%, P<0.001) and the individual endpoints of cardiac death (HR: 0.84, 95% CI: 0.75-0.95, I2=0%, P=0.007) and HHF (HR: 0.69, 95% CI: 0.62-0.77, I2=0%, P<0.001).
CONCLUSIONS: SGLT-2 inhibitors reduced the risk of cardiac death in patients with HFrEF but not in those with HFpEF.

Keywords: SGLT-2 inhibitor; cardiac death; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; meta-analysis; rehospitalization for heart failure

DOI: https://doi.org/10.1016/j.diabres.2022.109871

Circ Heart Fail. 2022 Apr 14. 101161CIRCHEARTFAILURE121008547

Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress.

Mateusz M Tomczyk, Kyle G Cheung, Bo Xiang, Nahid Tamanna, Ana L Fonseca Teixeira, Prasoon Agarwal, Stephanie M Kereliuk, Victor Spicer, Ligen Lin, Jason Treberg, Qiang Tong, Vernon W Dolinsky.

BACKGROUND: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.
METHODS: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4-10).
RESULTS: Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress.
CONCLUSIONS: Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.

Keywords: acetylation; dilated cardiomyopathy; doxorubicin; mitochondria; superoxide

DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.121.008547

Int J Mol Sci. 2022 Mar 25. pii: 3587. [Epub ahead of print]23(7):

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus.

Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Satoshi Akagi, Yukihiro Saito, Kentaro Ejiri, Naoaki Matsuo, Keishi Ichikawa, Keiichiro Iwasaki, Takanori Naito, Yusuke Namba, Masatoki Yoshida, Hiroki Sugiyama, Hiroshi Ito.

There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

Keywords: SGLT2 inhibitor; heart failure; lipotoxicity

DOI: https://doi.org/10.3390/ijms23073587

Nutrients. 2022 Mar 22. pii: 1322. [Epub ahead of print]14(7):

Ketogenic Diet and Cardiac Substrate Metabolism.

Thien Vinh Luong, Caroline Bruun Abild, Maj Bangshaab, Lars Christian Gormsen, Esben Søndergaard.

The ketogenic diet (KD) entails a high intake of fat, moderate intake of protein, and a very limited intake of carbohydrates. Ketogenic dieting has been proposed as an effective intervention for type 2 diabetes and obesity since glycemic control is improved and sustained weight loss can be achieved. Interestingly, hyperketonemia is also associated with beneficial cardiovascular effects, possibly caused by improved cardiac energetics and reduced oxygen use. Therefore, the KD has the potential to both treat and prevent cardiovascular disease. However, the KD has some adverse effects that could counteract the beneficial cardiovascular properties. Of these, hyperlipidemia with elevation of triglycerides and LDL cholesterol levels are the most important. In addition, poor diet adherence and lack of knowledge regarding long-term effects may also reduce the broader applicability of the KD. The objective of this narrative review is to provide insights into the KD and its effects on myocardial ketone body utilization and, consequently, cardiovascular health.

Keywords: diabetic cardiomyopathy; heart; heart failure; ketogenic diet; ketone bodies; metabolism

DOI: https://doi.org/10.3390/nu14071322

Commun Biol. 2022 Apr 12. 5(1): 349

The intra-mitochondrial O-GlcNAcylation system rapidly modulates OXPHOS function and ROS release in the heart.

Justine Dontaine, Asma Bouali, Frederic Daussin, Laurent Bultot, Didier Vertommen, Manon Martin, Raahulan Rathagirishnan, Alexanne Cuillerier, Sandrine Horman, Christophe Beauloye, Laurent Gatto, Benjamin Lauzier, Luc Bertrand, Yan Burelle.

Protein O-GlcNAcylation is increasingly recognized as an important cellular regulatory mechanism, in multiple organs including the heart. However, the mechanisms leading to O-GlcNAcylation in mitochondria and the consequences on their function remain poorly understood. In this study, we use an in vitro reconstitution assay to characterize the intra-mitochondrial O-GlcNAc system without potential cytoplasmic confounding effects. We compare the O-GlcNAcylome of isolated cardiac mitochondria with that of mitochondria acutely exposed to NButGT, a specific inhibitor of glycoside hydrolase. Amongst the 409 O-GlcNAcylated mitochondrial proteins identified, 191 display increased O-GlcNAcylation in response to NButGT. This is associated with enhanced Complex I (CI) activity, increased maximal respiration in presence of pyruvate-malate, and a striking reduction of mitochondrial ROS release, which could be related to O-GlcNAcylation of specific subunits of ETC complexes (CI, CIII) and TCA cycle enzymes. In conclusion, our work underlines the existence of a dynamic mitochondrial O-GlcNAcylation system capable of rapidly modifying mitochondrial function.

DOI: https://doi.org/10.1038/s42003-022-03282-3

Front Pharmacol. 2022 ;13 850542

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway.

George J Dugbartey, Quinsker L Wonje, Karl K Alornyo, Louis Robertson, Ismaila Adams, Vincent Boima, Samuel D Mensah.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Keywords: alpha-lipoic acid (ALA); anti-diabetic therapy; diabetic cardiomyopathy (DCM); triple combination therapy; type 2 diabetes mellitus (T2DM)

DOI: https://doi.org/10.3389/fphar.2022.850542

Cardiovasc Ther. 2022 ;2022 7014680

Advanced Glycation End Product Blocker Drugs Have a Great Potential to Prevent Diabetic Cardiomyopathy in an Animal Model of Diabetes Mellitus Type-2.

Amir Hossein Heydari, Mojtaba Fathi, Sophia Heydari, Mohammad Esmaeil Heidari.

Introduction: Sphingosine 1 phosphate (S1P) is a product of the sphingosine kinase 1 (SphK1) enzyme. Increased S1P can lead to tissue fibrosis that is also one of the pathways for developing diabetic cardiomyopathy. Advanced glycation end products (AGEs) increase S1P in cells. The study is aimed at using aminoguanidine (AG) as an AGEs blocker drug to prevent diabetic cardiomyopathy. Materials and methods. 210 rats were enrolled in the study. Diabetes mellitus type-2 was induced, and rats were divided into AG treated diabetic and nondiabetic groups. The heart histology was assessed with Masson's trichrome and hematoxylin-eosin staining. Cardiac function was measured with transthoracic echocardiography. S1P level and SphK1 gene expression were measured by western-blot and RT-qPCR, respectively.
Results: Results showed that S1P level increases in diabetes, and its augmentation in cardiac tissue with K6PC-5 leads to cardiac fibrosis. 50 and 200 mg/kg of AG prevented cardiac fibrosis, but 100 mg/kg had no significant preventive effect. AG suppressed the SphK1 gene expression and reduced the fibrotic effect of S1P. AG preserved cardiac function by keeping ejection fraction and fractional shortening within the normal range in diabetic rats.
Conclusion: AG has a suppressor effect on SphK1 gene expression besides its AGEs blocker role. AG is a potential drug to use in diabetic patients for preventing the development of diabetic cardiomyopathy. Other drugs that have AGEs or S1P blocker effects are a good choice for diabetic cardiomyopathy prevention.

DOI: https://doi.org/10.1155/2022/7014680