New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis

Abstract

Introduction

Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC.

Methods

Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups.

Results

LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats.

Conclusion

LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.

Keywords:

• type 2 diabetes mellitus
• diabetic cardiomyopathy
• anti-TNF-α therapy
• cardiac dysfunction
• heart hypertrophy
• Zucker diabetic fatty rat

Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Instituto Nacional de Ciência e Tecnologia de Fármacose Medicamentos (INCT-INOFAR), Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO).

Abbreviations

ACh, acetylcholine; ACh_max, maximal vascular relaxation to acetylcholine; AGE, advanced glycation endproducts; ANOVA, analysis of variance; AP-1, activator protein-1; AWTd, anterior wall thickness at diastole; CO, cardiac output; DBP, diastolic blood pressure; DC, diabetic cardiomyopathy; DPP4, dipeptidyl peptidase 4; dP/dt, rate of change of intraventricular pressure; EF, ejection fraction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HR, heart rate; iNOS, inducible nitric oxide synthase; ip, intraperitoneal; LV, left ventricle; LVEDP, left ventricle end diastolic pressure; LVIDd, left ventricle internal diameter at diastole; LVSP, left ventricle systolic pressure; NAH, N-acylhydrazone; NFκB, nuclear factor κB; oxLDL, oxidized low-density lipoprotein; Phe, phenylephrine; PWTd, posterior wall thickness at diastole; QUICKI, quantitative insulin sensitivity check index; RAGE, receptor for advanced glycation endproducts; RWT, relative wall thickness; SBP, systolic blood pressure; SEM, standard error of the mean; T2DM, type 2 diabetes mellitus; TNF, tumor necrosis factor; TyG, triglyceride–glucose index; ZDF, Zucker diabetic fatty; ZL, Zucker lean.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, agree to the journal in which the paper was submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Marina MC Silva reports grants from CAPES, during the conduct of the study. Gisele Zapata-Sudo reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro - FAPERJ, and Instituto Nacional de Ciência e Tecnologia em Fármacos e Medicamentos (INCT-INOFAR), during the conduct of the study. The authors declare no other possible conflicts of interest in this work.