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

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.

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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/dt max :

Maximal slope of the systolic pressure increment

dP/dt min :

Maximal slope of the diastolic pressure decrement

E max :

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

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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).

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Correspondence to Yong Seon Choi.

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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.

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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.

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Oh, J.E., Jun, J.H., Hwang, H.J. et al. Dexmedetomidine restores autophagy and cardiac dysfunction in rats with streptozotocin-induced diabetes mellitus. Acta Diabetol 56, 105–114 (2019). https://doi.org/10.1007/s00592-018-1225-9

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Keywords

  • Autophagy
  • Cardiac function
  • Diabetic cardiomyopathy
  • Dexmedetomidine
  • Type 1 diabetes