Dexmedetomidine restores autophagy and cardiac dysfunction in rats with streptozotocin-induced diabetes mellitus
Dexmedetomidine (DEX), a highly selective and potent α2-adrenergic receptor agonist, has anti-apoptotic, anti-inflammatory, and anti-oxidative stress effects in diabetes mellitus (DM) rats. The underlying molecular mechanisms and signaling pathways of diabetic cardiomyopathy remain poorly understood. This study aimed to elucidate the effect of DEX on cardiac function in DM rats.
Eight-week-old male Sprague Dawley rats were divided into three groups: control (n = 5), diabetes (DM, n = 7), and diabetes + DEX (DM + DEX, n = 10). DM was induced via intraperitoneal injection of streptozotocin (70 mg/kg); at 3 days later, DEX (1 µg/kg/h) was administered for 4 weeks. Cardiac function was evaluated using pressure–volume loop analysis and echocardiography. Left ventricular (LV) histological sections were used to analyze the interstitial collagen fraction. Using the LV samples, we performed a western blot analysis to evaluate signaling pathways and autophagic markers.
The DM group had lower body weight and higher blood glucose level and heart weight/body weight ratio than the control group. However, metabolic changes did not differ between the DM and DM + DEX groups. Pressure–volume loop analysis and echocardiography showed impaired cardiac function, evidenced by a decrease in systolic and diastolic function, in both DM groups. DEX treatment in DM rats was associated with increased LV end-systolic pressure, LV contractility, cardiac output, and relaxed LV function compared with that in non-treated DM rats. LC3B and autophagy-related gene (ATG) proteins increased in the hearts of DM rats compared with the hearts of control rats. However, DEX reduced the expression of LC3B and ATG proteins in the hearts of DM rats. Increased p-ERK and decreased p-AKT were reduced in the hearts of DEX-treated DM rats.
DEX reduces cardiac dysfunction and impaired autophagy in DM rats. This study reinforces our understanding of the potential anti-autophagic effect of DEX in patients with diabetic cardiomyopathy.
KeywordsAutophagy Cardiac function Diabetic cardiomyopathy Dexmedetomidine Type 1 diabetes
Extracellular signal-regulated kinase
- PV loop
LV end-systolic pressure
Maximal slope of the systolic pressure increment
Maximal slope of the diastolic pressure decrement
Slope of end-systolic pressure–volume relationship
Preload recruitable stroke work
End-diastolic pressure–volume relationship
LV end-diastolic dimension
LV end-systolic dimension
- TDI E/E′
Ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity
Ratio between early (E)-to-late (A) diastolic mitral inflow
Mitogen-activated protein kinase
This study was supported by the following Grants: the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (NRF2014R1A1A3053428).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All animal procedures were approved by the Committee for the Care and Use of Laboratory Animals, Yonsei University College of Medicine (No. 2015–0129), and were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.
Human and animal rights
This article does not contain any studies with human participants performed by any of the authors. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution.
For this type of study formal consent is not required.
- 15.Sanders RD, Maze M (2007) Alpha2-adrenoceptor agonists. Curr Opin Investig Drugs 8:25–33Google Scholar
- 17.Arslan M, Comu FM, Kip G et al (2014) Effect of dexmedetomidine on erythrocyte deformability during ischaemia–reperfusion injury of heart in diabetic rats. Bratisl Lek Listy 115:494–497Google Scholar
- 24.Engelhard K, Werner C, Eberspacher E et al (2003) The effect of the alpha 2-agonist dexmedetomidine and the N-methyl-d-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg 96:524–531CrossRefGoogle Scholar
- 25.Ding D, Xu S, Zhang H et al (2018) 3-Methyladenine and dexmedetomidine reverse lipopolysaccharide-induced acute lung injury through the inhibition of inflammation and autophagy. Exp Ther Med 15:3516–3522Google Scholar
- 39.Fei AH, Wang FC, Wu ZB, Pan SM (2016) Phosphocreatine attenuates angiotensin II-induced cardiac fibrosis in rat cardiomyocytes through modulation of MAPK and NF-kappaB pathway. Eur Rev Med Pharmacol Sci 20:2726–2733Google Scholar