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

Al-Damry, Nouf T.; Attia, Hala; Al-Rasheed, Nawal M.; Mohamad, Raeesa A.; Al-Amin, Maha A.; Dizmiri, Nduna; Atteya, Muhammad

doi:10.1016/j.biopha.2018.07.126

Cited by 36 publications

(29 citation statements)

References 59 publications

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“…Even so, the inhibition of both AMPK and PGC1α partially reversed the above effects exerted by melatonin, suggesting that the AMPK/PGC1α pathway is involved in the anti-apoptotic protective effects of melatonin against DOX cardiotoxicity [ 33 ]. In addition, Al-Damry’s group demonstrated that sitagliptin protected against cardiac apoptosis by activating LKB/AMPK/Akt pathway as well as reducing the activity of GSK3β and p38α/MAPK [ 34 ].…”

Section: Protective Mechanisms Of Ampk Signaling In Myocardiummentioning

confidence: 99%

“…The results suggested that MLD may suppress oxidative stress induced by hyperglycemia and MI/R by activating AMPK/Nrf2 signaling pathway, and eventually protect against diabetic-associated cardiomyopathy. Al-Damry’s group demonstrated that sitagliptin protects against diabetic cardiomyopathy by attenuating apoptosis via activation of LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK [ 34 ]. Notably, cardio-myopathy may sometimes manifest hypertrophy of the heart muscle, which may contribute to heart failure if not treated in time.…”

Section: Ampk and Aging-related Cvdmentioning

confidence: 99%

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Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Tian¹,

Ma²,

Yin³

et al. 2020

Aging and disease

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Aging is a pivotal risk factor for developing cardiovascular diseases (CVD) due to the lifelong exposure to various risk factors that may affect the heart and vasculature during aging. AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, is a pivotal endogenous energy regulator that protects against various pathological alterations. In this report, we first introduced the protective mechanisms of AMPK signaling in myocardium, such as oxidative stress, apoptosis, inflammation, autophagy and inflammatory response. Next, we introduced the potential correlation between AMPK and cardiac aging. Then, we highlighted the roles of AMPK signaling in cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Lastly, some potential directions and further perspectives were expanded. The information extends our understanding on the protective roles of AMPK in myocardial aging, which may contribute to the design of drug targets and sheds light on potential treatments of AMPK for aging-related CVD.

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Section: Protective Mechanisms Of Ampk Signaling In Myocardiummentioning

confidence: 99%

Section: Ampk and Aging-related Cvdmentioning

confidence: 99%

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Tian¹,

Ma²,

Yin³

et al. 2020

Aging and disease

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“…Akt and MAPK are two main signaling pathways which participate in cardiomyocyte apoptosis [18,44]. The mammalian MAPK family, including Erk1/2, p38 MAPK, and JNK have been identified so far.…”

Section: Discussionmentioning

confidence: 99%

“…Mitogen-activated protein kinases (MAPK) signal transduction pathways are involved in the regulation of apoptosis in cardiac myocytes [18]. Thus, we investigated whether these pathways were modified in Cypher knockdown H9c2 cells and western blotting was used to detect the phosphorylation levels of c-Jun NH2-terminal kinase (JNK), extracellular regulated protein kinases 1/2 (Erk1/2) and p38 MAPK, which are key mediators of cardiac apoptosis.…”

Section: Mapk and Akt Participated In Downregulation Of Cypher Inducementioning

confidence: 99%

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

Xuan

Wang

et al. 2020

Int. J. Med. Sci.

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Background: Dilated cardiomyopathy (DCM) is considered as the most common form of non-ischemic cardiomyopathy with a high mortality worldwide. Cytoskeleton protein Cypher plays an important role in maintaining cardiac function. Genetic studies in human and animal models revealed that Cypher is involved in the development of DCM. However, the underlying molecular mechanism is not fully understood. Accumulating evidences suggest that apoptosis in myocytes may contribute to DCM. Thus, the purpose of this study is to define whether lack of Cypher in cardiomyocytes can elevate apoptosis signaling and lead to DCM eventually. Methods and Results: Cypher-siRNA sufficiently inhibited Cypher expression in cardiomyocytes. TUNEL-positive cardiomyocytes were increased in both Cypher knockdown neonatal rat cardiomyocytes and Cypher knockout mice hearts, which were rare in the control group. Flow cytometry further confirmed that downregulation of Cypher significantly increased myocytes apoptosis in vitro. Cell counting kit-8 assay revealed that Cypher knockdown in H9c2 cells significantly reduced cell viability. Cypher knockdown was found to increase cleaved caspase-3 expression and suppress p21, ratio of bcl-2 to Bax. Cypher-deficiency induced apoptosis was linked to downregulation of Akt activation and elevated p-p38 MAPK accumulation. Pharmacological activation of Akt with SC79 attenuated apoptosis with enhanced phosphorylation of Akt and reduced p-p38 MAPK and Bax expression. Conclusions: Downregulation of Cypher participates in the promotion of cardiomyocytes apoptosis through inhibiting Akt dependent pathway and enhancing p38 MAPK phosphorylation. These findings may provide a new potential therapeutic strategy for the treatment of DCM.

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“…This protective effect is related to other pathways like Bcl-2 associated X Protein (Bax)/B-cell lymphoma-2 (Bcl-2) (Li et al, 2018b). Sitagliptin was reported to inhibit the liver kinase B-1 (LKB-1)/ 5′-AMP-activated protein kinas (AMPK)/Akt pathway, activate the glycogen synthase kinase-3b (GSK3-b) and p38 MAPK pathways, thereby preventing apoptosis and cardiomyopathy (Al-Damry et al, 2018). Inactivation of the TGFb-activated kinase 1(TAK1)-p38 MAPK/c-Jun N-terminal kinase (JNK) signaling pathway protects the heart from cardiac hypertrophy and dysfunction (Li et al, 2016).…”

Section: Ampk/foxo and Related Pathwaysmentioning

confidence: 99%

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases

Guo

Jiang

et al. 2020

Front. Pharmacol.

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Chinese medicine is a national treasure that has been passed down for thousands of years in China. According to the statistics of the World Health Organization, there are currently four billion people in the world who use Chinese medicine to treat diseases, accounting for 80% of the world's total population. However, the obscurity of its theory, its unmanageable quality, its complex compositions, and the unknown effective substances and mechanisms are great obstacles to the internationalization of Chinese medicine. Here, we propose a new strategy for the development of Chinese medicine: the clinical prescription (C)-protein (P)-small-molecule (S)-disease (D) strategy, namely the CPSD strategy. The strategy uses clinical prescriptions as the source of medicine and uses computer simulation technology to find small-molecule drugs targeting therapeutic proteins for treating specific diseases so as to deepen awareness of the value of Chinese medicine. At the same time, this article takes cardiovascular drug development as an example to introduce the application of CPSD, which will be instrumental in the further development, modernization, and internationalization of Chinese medicine.

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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

Cited by 36 publications

References 59 publications

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases

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