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Published on: September 18, 2017
Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway
Xi Chen1, Long Ren2, Xing Liu2
1Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China; Department of Pharmacy, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Insights
Ranolazine treatment protects against diabetic cardiomyopathy (DCM) by activating the NOTCH1/NRG1 pathway, reducing cardiac injury and apoptosis. This study reveals new mechanisms for DCM treatment.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Diabetic cardiomyopathy (DCM) is a serious diabetes complication leading to heart failure and sudden death.
- Ranolazine, an antianginal drug, shows potential for cardiovascular diseases, but its mechanism in DCM is unknown.
Purpose of the Study:
- To investigate the effects and underlying mechanisms of ranolazine in treating diabetic cardiomyopathy.
- To explore ranolazine's impact on cardiac function, apoptosis, and specific molecular pathways in DCM.
Main Methods:
- DCM rats were treated with varying doses of ranolazine for 12 weeks.
- Assessed cardiac injury via echocardiography, CT, and histological staining; measured apoptosis using TUNEL and flow cytometry.
- Analyzed expression of apoptosis-related proteins (Bcl-2, Bax, Caspase-3) and signaling molecules (NOTCH1, NRG1) via western blot and qRT-PCR; utilized a NOTCH1 inhibitor (DAPT) to elucidate mechanisms.
Main Results:
- Ranolazine treatment did not cause weight loss and significantly reduced blood glucose levels in DCM rats.
- Ranolazine effectively prevented diabetes-induced cardiac injury and decreased cellular apoptosis.
- Ranolazine activated NOTCH1, which in turn activated NRG1, inhibiting downstream apoptosis pathways; DAPT partially blocked these effects.
Conclusions:
- This study is the first to show ranolazine protects against DCM-induced apoptosis via the NOTCH1/NRG1 signaling pathway.
- Ranolazine represents a potential therapeutic agent for DCM by targeting the NOTCH1/NRG1 pathway.
- New molecular mechanisms involved in DCM pathogenesis and treatment have been identified.
Aims:
Diabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular diseases. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM.
Materials And Methods:
DCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine.
Key Findings:
Compared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression.
Significance:
To our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.
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