Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Acta Diabetologica
Published in: Acta Diabetologica 1/2019

01-01-2019 | Original Article

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

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

Published in: Acta Diabetologica | Issue 1/2019

Login to get access

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.
Literature
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 1852:232–242CrossRefPubMed
2.
Kobayashi S, Liang Q (2015) Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852:252–261CrossRefPubMed
3.
Ouyang C, You J, Xie Z (2014) The interplay between autophagy and apoptosis in the diabetic heart. J Mol Cell Cardiol 71:71–80CrossRefPubMed
4.
Carollo DS, Nossaman BD, Ramadhyani U (2008) Dexmedetomidine: a review of clinical applications. Curr Opin Anaesthesiol 21:457–461CrossRefPubMed
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:e0151620CrossRefPubMedPubMedCentral
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 12:1270021CrossRefPubMedPubMedCentral
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 10:27828CrossRefPubMed
8.
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477CrossRefPubMed
9.
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 13:619–624CrossRefPubMed
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 54:348–359CrossRefPubMed
12.
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:e112695CrossRefPubMedPubMedCentral
14.
15.
Sanders RD, Maze M (2007) Alpha2-adrenoceptor agonists. Curr Opin Investig Drugs 8:25–33PubMed
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:e0127411CrossRefPubMedPubMedCentral
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 115:494–497PubMed
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 103:318–327CrossRefPubMed
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 74:538–545CrossRefPubMed
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 1822:537–545CrossRefPubMed
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 44:946–953CrossRefPubMed
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 69:228–235CrossRefPubMed
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 14:797–803CrossRefPubMedPubMedCentral
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 96:524–531CrossRefPubMed
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 15:3516–3522PubMedPubMedCentral
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 95:885–893CrossRefPubMed
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 11:197CrossRefPubMedPubMedCentral
28.
Martinet W, Knaapen MW, Kockx MM, De Meyer GR (2007) Autophagy in cardiovascular disease. Trends Mol Med 13:482–491CrossRefPubMed
29.
Terman A, Brunk UT (2005) Autophagy in cardiac myocyte homeostasis, aging, and pathology. Cardiovasc Res 68:355–365CrossRefPubMed
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 13:1765–1773CrossRefPubMed
31.
Kanamori H, Takemura G, Goto K et al (2015) Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes. Autophagy 11:1146–1160CrossRefPubMedPubMedCentral
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:e30450CrossRefPubMedPubMedCentral
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 60:1770–1778CrossRefPubMedPubMedCentral
34.
35.
Javadov S, Jang S, Agostini B (2014) Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives. Pharmacol Ther 144:202–225CrossRefPubMedPubMedCentral
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 258:134–146CrossRefPubMed
37.
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 14:109CrossRefPubMedPubMedCentral
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 20:2726–2733PubMed
40.
Sager HB, Hulsmans M, Lavine KJ et al (2016) Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res 119:853–864CrossRefPubMedPubMedCentral
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 39:371–384CrossRefPubMed
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:e0119214CrossRefPubMedPubMedCentral
43.
44.
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 83:653–660CrossRefPubMed
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 58:1937–1948CrossRefPubMed
47.
Ravingerova T, Barancik M, Strniskova M (2003) Mitogen-activated protein kinases: a new therapeutic target in cardiac pathology. Mol Cell Biochem 247:127–138CrossRefPubMed
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 16:281–314CrossRefPubMed
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 119:506–516CrossRefPubMed
Metadata
Title
Dexmedetomidine restores autophagy and cardiac dysfunction in rats with streptozotocin-induced diabetes mellitus
Authors
Ju Eun Oh
Ji Hae Jun
Hye Jeong Hwang
Eun Jung Shin
Young Jun Oh
Yong Seon Choi
Publication date
01-01-2019
Publisher
Springer Milan
Published in
Acta Diabetologica / Issue 1/2019
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-018-1225-9

Other articles of this Issue 1/2019

Acta Diabetologica 1/2019 Go to the issue

Original Article

Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats

Original Article

Ethnicity-specific association of BMI levels at diagnosis of type 2 diabetes with cardiovascular disease and all-cause mortality risk

Letter to the Editor

Comment on “Characterization of circulating leukocytes and correlation of leukocyte subsets with metabolic parameters 1 and 5 years after diabetes diagnosis”

Original Article

Expectations and fear of diabetes-related long-term complications in people with type 2 diabetes at primary care level

Letter to the Editor

Reply to Comment to: The relationship between sleep and cognitive function in patients with prediabetes and type 2 diabetes

Review Article

DPP-4 inhibitors for the treatment of type 2 diabetes: a methodology overview of systematic reviews

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits