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

Gizele Cabral Costa1 ,* Tadeu Lima Montagnoli2 ,* Jaqueline Soares Da Silva,2 Allan Kardec Nogueira de Alencar,2 Luis Eduardo Reina Gamba,2 Bryelle Eccard Oliveira Alves,1,2 Marina Moraes Carvalho da Silva,2 Margarete Manhães Trachez,2 José Hamilton M do Nascimento,2,3 Pedro Moreno Pimentel-Coelho,3 Rosália Mendez-Otero,3 Lidia Moreira Lima,2 Eliezer J Barreiro,2 Roberto Takashi Sudo,2 Gisele Zapata-Sudo1,2 1Programa de Pós-Graduação em Medicina (Cardiologia), Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; 2Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; 3Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil*These authors contributed equally to this workCorrespondence: Gisele Zapata-SudoInstituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-590, BrazilTel/ Fax +55-21-39386505Email gsudo@icb.ufrj.brIntroduction: 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