Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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

References

  1. Varga ZV, Giricz Z, Liaudet L, Hasko G, Ferdinandy P, Pacher P (2015) Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852:232–242

    Article  PubMed  CAS  Google Scholar 

  2. Kobayashi S, Liang Q (2015) Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852:252–261

    Article  PubMed  CAS  Google Scholar 

  3. Ouyang C, You J, Xie Z (2014) The interplay between autophagy and apoptosis in the diabetic heart. J Mol Cell Cardiol 71:71–80

    Article  PubMed  CAS  Google Scholar 

  4. Carollo DS, Nossaman BD, Ramadhyani U (2008) Dexmedetomidine: a review of clinical applications. Curr Opin Anaesthesiol 21:457–461

    Article  PubMed  Google Scholar 

  5. Zeng X, Wang H, Xing X, Wang Q, Li W (2016) Dexmedetomidine protects against transient global cerebral ischemia/reperfusion induced oxidative stress and inflammation in diabetic rats. PLoS One 11:e0151620

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Erbatur ME, Sezen SC, Bayraktar AC, Arslan M, Kavutcu M, Aydin ME (2017) Effects of dexmedetomidine on renal tissue after lower limb ischemia reperfusion injury in streptozotocin induced diabetic rats. Libyan J Med 12:1270021

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kip G, Celik A, Bilge M et al (2015) Dexmedetomidine protects from post-myocardial ischaemia reperfusion lung damage in diabetic rats. Libyan J Med 10:27828

    Article  PubMed  Google Scholar 

  8. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477

    Article  PubMed  CAS  Google Scholar 

  9. Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Nakai A, Yamaguchi O, Takeda T et al (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624

    Article  PubMed  CAS  Google Scholar 

  11. Wang H, Wang J, Qu H et al (2016) In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway. Endocrine 54:348–359

    Article  PubMed  CAS  Google Scholar 

  12. Xu Z, Sun J, Tong Q et al (2016) The role of ERK1/2 in the development of diabetic cardiomyopathy. Int J Mol Sci 17:2001. https://doi.org/10.3390/ijms17122001

    Article  PubMed Central  CAS  Google Scholar 

  13. Zhang Y, Wang Y, Yang K et al (2014) BMP4 increases the expression of TRPC and basal [Ca2+]i via the p38MAPK and ERK1/2 pathways independent of BMPRII in PASMCs. PLoS One 9:e112695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Gallagher LE, Williamson LE, Chan EY (2016) Advances in autophagy regulatory mechanisms. Cells 5:24. https://doi.org/10.3390/cells5020024

    Article  PubMed Central  CAS  Google Scholar 

  15. Sanders RD, Maze M (2007) Alpha2-adrenoceptor agonists. Curr Opin Investig Drugs 8:25–33

    PubMed  CAS  Google Scholar 

  16. Venot M, Weis L, Clec’h C et al (2015) Acute kidney injury in severe sepsis and septic shock in patients with and without diabetes mellitus: a multicenter study. PLoS One 10:e0127411

    Article  PubMed  PubMed Central  CAS  Google 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 115:494–497

    PubMed  CAS  Google Scholar 

  18. Riquelme JA, Westermeier F, Hall AR et al (2016) Dexmedetomidine protects the heart against ischemia–reperfusion injury by an endothelial eNOS/NO dependent mechanism. Pharmacol Res 103:318–327

    Article  PubMed  CAS  Google Scholar 

  19. Okada H, Kurita T, Mochizuki T, Morita K, Sato S (2007) The cardioprotective effect of dexmedetomidine on global ischaemia in isolated rat hearts. Resuscitation 74:538–545

    Article  PubMed  CAS  Google Scholar 

  20. Ibacache M, Sanchez G, Pedrozo Z et al (2012) Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. Biochim Biophys Acta 1822:537–545

    Article  PubMed  CAS  Google Scholar 

  21. Sun Y, Jiang C, Jiang J, Qiu L (2017) Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. Clin Exp Pharmacol Physiol 44:946–953

    Article  PubMed  CAS  Google Scholar 

  22. Behmenburg F, Pickert E, Mathes A et al (2017) The cardioprotective effect of dexmedetomidine in rats is dose-dependent and mediated by BKCa channels. J Cardiovasc Pharmacol 69:228–235

    Article  PubMed  CAS  Google Scholar 

  23. Cheng XY, Gu XY, Gao Q, Zong QF, Li XH, Zhang Y (2016) Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury. Mol Med Rep 14:797–803

    Article  PubMed  PubMed Central  CAS  Google 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 96:524–531

    Article  PubMed  CAS  Google 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 15:3516–3522

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Shen M, Wang S, Wen X et al (2017) Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother 95:885–893

    Article  PubMed  CAS  Google Scholar 

  27. Luo C, Ouyang MW, Fang YY et al (2017) Dexmedetomidine protects mouse brain from ischemia–reperfusion injury via inhibiting neuronal autophagy through up-regulating HIF-1alpha. Front Cell Neurosci 11:197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Martinet W, Knaapen MW, Kockx MM, De Meyer GR (2007) Autophagy in cardiovascular disease. Trends Mol Med 13:482–491

    Article  PubMed  CAS  Google Scholar 

  29. Terman A, Brunk UT (2005) Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 68:355–365

    Article  PubMed  CAS  Google Scholar 

  30. Xiao T, Luo J, Wu Z, Li F, Zeng O, Yang J (2016) Effects of hydrogen sulfide on myocardial fibrosis and PI3K/AKT1-regulated autophagy in diabetic rats. Mol Med Rep 13:1765–1773

    Article  PubMed  CAS  Google Scholar 

  31. Kanamori H, Takemura G, Goto K et al (2015) Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes. Autophagy 11:1146–1160

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Eguchi M, Kim YH, Kang KW et al (2012) Ischemia–reperfusion injury leads to distinct temporal cardiac remodeling in normal versus diabetic mice. PLoS One 7:e30450

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Xie Z, Lau K, Eby B et al (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60:1770–1778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Xu X, Kobayashi S, Chen K et al (2013) Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem 288:18077–18092

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Javadov S, Jang S, Agostini B (2014) Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Pharmacol Ther 144:202–225

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Wang S, Luo M, Zhang Z et al (2016) Zinc deficiency exacerbates while zinc supplement attenuates cardiac hypertrophy in high-fat diet-induced obese mice through modulating p38 MAPK-dependent signaling. Toxicol Lett 258:134–146

    Article  PubMed  CAS  Google Scholar 

  37. Zhang N, Yang Z, Yuan Y et al (2015) Naringenin attenuates pressure overload-induced cardiac hypertrophy. Exp Ther Med 10:2206–2212

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Zhang L, Ding WY, Wang ZH et al (2016) Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. J Transl Med 14:109

    Article  PubMed  PubMed Central  CAS  Google 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 20:2726–2733

    PubMed  Google Scholar 

  40. Sager HB, Hulsmans M, Lavine KJ et al (2016) Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res 119:853–864

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Martinez PF, Bonomo C, Guizoni DM et al (2016) Modulation of MAPK and NF-954;B signaling pathways by antioxidant therapy in skeletal muscle of heart failure rats. Cell Physiol Biochem 39:371–384

    Article  PubMed  CAS  Google Scholar 

  42. Thandavarayan RA, Giridharan VV, Arumugam S et al (2015) Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. PLoS One 10:e0119214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Kehat I, Molkentin JD (2010) Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann N Y Acad Sci 1188:96–102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Mutlak M, Kehat I (2015) Extracellular signal-regulated kinases 1/2 as regulators of cardiac hypertrophy. Front Pharmacol 6:149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Lakshmanan AP, Harima M, Sukumaran V et al (2012) Modulation of AT-1R/AMPK-MAPK cascade plays crucial role for the pathogenesis of diabetic cardiomyopathy in transgenic type 2 diabetic (Spontaneous Diabetic Torii) rats. Biochem Pharmacol 83:653–660

    Article  PubMed  CAS  Google Scholar 

  46. Zhang C, Huang Z, Gu J et al (2015) Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. Diabetologia 58:1937–1948

    Article  PubMed  CAS  Google Scholar 

  47. Ravingerova T, Barancik M, Strniskova M (2003) Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol Cell Biochem 247:127–138

    Article  PubMed  CAS  Google Scholar 

  48. Gerits N, Kostenko S, Moens U (2007) In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice. Transgenic Res 16:281–314

    Article  PubMed  CAS  Google Scholar 

  49. Perez-Zoghbi JF, Zhu W, Grafe MR, Brambrink AM (2017) Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth 119:506–516

    Article  PubMed  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Ju Eun Oh, Ji Hae Jun, Hye Jeong Hwang, Eun Jung Shin, Young Jun Oh & Yong Seon Choi

  2. Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Young Jun Oh & Yong Seon Choi

Authors
  1. Ju Eun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Hae Jun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hye Jeong Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun Jung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young Jun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Seon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Seon Choi.

Ethics declarations

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.

Additional information

Managed by Massimo Porta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-018-1225-9

Keywords

Search

Navigation