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Acta Diabetologica

, Volume 56, Issue 1, pp 105–114 | Cite as

Dexmedetomidine restores autophagy and cardiac dysfunction in rats with streptozotocin-induced diabetes mellitus

  • Ju Eun Oh
  • Ji Hae Jun
  • Hye Jeong Hwang
  • Eun Jung Shin
  • Young Jun Oh
  • Yong Seon ChoiEmail author
Original Article

Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Autophagy Cardiac function Diabetic cardiomyopathy Dexmedetomidine Type 1 diabetes 

Abbreviations

DM

Diabetes mellitus

DCM

Diabetic cardiomyopathy

LV

Left ventricular

DEX

Dexmedetomidine

STZ

Streptozotocin

ECL

Enhanced chemiluminescence

ERK

Extracellular signal-regulated kinase

PV loop

Pressure–volume loop

HR

Heart rate

LVESP

LV end-systolic pressure

dP/dtmax

Maximal slope of the systolic pressure increment

dP/dtmin

Maximal slope of the diastolic pressure decrement

Emax

Slope of end-systolic pressure–volume relationship

SW

Stroke work

EF

Ejection fraction

SV

Stroke volume

CO

Cardiac output

PRSW

Preload recruitable stroke work

EDPVR

End-diastolic pressure–volume relationship

LVEDD

LV end-diastolic dimension

LVESD

LV end-systolic dimension

ATG

Autophagy-related gene

TDI E/E

Ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity

E/A

Ratio between early (E)-to-late (A) diastolic mitral inflow

MAPK

Mitogen-activated protein kinase

Notes

Acknowledgements

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.

Ethical approval

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.

Informed consent

For this type of study formal consent is not required.

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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Ju Eun Oh
    • 1
  • Ji Hae Jun
    • 1
  • Hye Jeong Hwang
    • 1
  • Eun Jung Shin
    • 1
  • Young Jun Oh
    • 1
    • 2
  • Yong Seon Choi
    • 1
    • 2
    Email author
  1. 1.Anesthesia and Pain Research InstituteYonsei University College of MedicineSeoulRepublic of Korea
  2. 2.Department of Anesthesiology and Pain MedicineYonsei University College of MedicineSeoulRepublic of Korea

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