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Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy.
Biomed Pharmacother. 2018 Nov; 107:347-358.BP

Abstract

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: hsalem@ksu.edu.sa.Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt.Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30099338

Citation

Al-Damry, Nouf T., et al. "Sitagliptin Attenuates Myocardial Apoptosis Via Activating LKB-1/AMPK/Akt Pathway and Suppressing the Activity of GSK-3β and p38α/MAPK in a Rat Model of Diabetic Cardiomyopathy." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 107, 2018, pp. 347-358.
Al-Damry NT, Attia HA, Al-Rasheed NM, et al. Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy. Biomed Pharmacother. 2018;107:347-358.
Al-Damry, N. T., Attia, H. A., Al-Rasheed, N. M., Al-Rasheed, N. M., Mohamad, R. A., Al-Amin, M. A., Dizmiri, N., & Atteya, M. (2018). Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 107, 347-358. https://doi.org/10.1016/j.biopha.2018.07.126
Al-Damry NT, et al. Sitagliptin Attenuates Myocardial Apoptosis Via Activating LKB-1/AMPK/Akt Pathway and Suppressing the Activity of GSK-3β and p38α/MAPK in a Rat Model of Diabetic Cardiomyopathy. Biomed Pharmacother. 2018;107:347-358. PubMed PMID: 30099338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy. AU - Al-Damry,Nouf T, AU - Attia,Hala A, AU - Al-Rasheed,Nawal M, AU - Al-Rasheed,Nouf M, AU - Mohamad,Raeesa A, AU - Al-Amin,Maha A, AU - Dizmiri,Nduna, AU - Atteya,Muhammad, Y1 - 2018/08/09/ PY - 2018/01/21/received PY - 2018/07/07/revised PY - 2018/07/24/accepted PY - 2018/8/14/pubmed PY - 2019/1/23/medline PY - 2018/8/13/entrez KW - AMPK KW - Akt KW - Diabetic cardiomyopathy KW - Glycogen synthase kinase-3β KW - Sitagliptin KW - p38MAPK SP - 347 EP - 358 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 107 N2 - The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/30099338/Sitagliptin_attenuates_myocardial_apoptosis_via_activating_LKB_1/AMPK/Akt_pathway_and_suppressing_the_activity_of_GSK_3β_and_p38α/MAPK_in_a_rat_model_of_diabetic_cardiomyopathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(18)30460-8 DB - PRIME DP - Unbound Medicine ER -