한빛사논문
- 조회320
Trong Kha Pham1,2,3, To Hoai T. Nguyen1,2, Joo Mi Yi4, Gwang Sil Kim5, Hyeong Rok Yun1, Hyoung Kyu Kim1,7 and Jong Chul Won6,7
1Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, South Korea.
2Department of Health Sciences and Technology, Graduate School, Inje University, Busan, South Korea.
3University of Science, Vietnam National University, Hanoi, Vietnam.
4Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, South Korea.
5Division of Cardiology, Department of Internal Medicine, Sanggye Paik Hospital, Inje University, Seoul, South Korea.
6Division of Endocrinology and Metabolism, Department of Internal Medicine, Sanggye Paik Hospital, Cardiovascular and Metabolic Disease Center, College of Medicine, Inje University, Seoul, South Korea.
7These authors contributed equally: Hyoung Kyu Kim, Jong Chul Won.
Corresponding author : Correspondence to Hyoung Kyu Kim or Jong Chul Won
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-19)
- 국내(교신)+국외 연구진
- 의약학 > 응용의학
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