PMID- 36481261 OWN - NLM STAT- MEDLINE DCOM- 20230106 LR - 20230216 IS - 1874-1754 (Electronic) IS - 0167-5273 (Linking) VI - 372 DP - 2023 Feb 1 TI - Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats. PG - 101-109 LID - S0167-5273(22)01873-3 [pii] LID - 10.1016/j.ijcard.2022.12.003 [doi] AB - BACKGROUND: Diabetic cardiomyopathy (DCM) is one of the severe complications of diabetes with no known biomarkers for early detection. Mitochondria-associated endoplasmic reticulum membranes (MAM) are less studied subcellular targets but an emerging area for exploration in metabolic disorders including DCM. We herein studied the role of MAMs and downstream mitochondrial functions in DCM. We also explored the efficacy of ferulic acid (FeA) against DCM via modulation of MAM and its associated signaling pathway. METHODS: The H9c2 cardiomyoblast cells were incubated with high concentration (33 mM) of d-glucose for 48 h to create a high glucose ambience in vitro. The expression of various critical proteins of MAM, mitochondrial function, oxidative phosphorylation (OxPhos) and the genesis of apoptosis were examined. The rats fed with high fat/high fructose/streptozotocin (single dose, i.p.) were used as a diabetic model and analyzed the insulin resistance and markers of cardiac hypertrophy and apoptosis. RESULTS: High glucose conditions caused the upregulation of MAM formation via PACS2, IP3R2, FUNDC1, and VDAC1 and decreased mitochondrial biogenesis, fusion and OxPhos. The upregulation of mitochondria-driven SMAC-HTRA2-ARTS-XIAP apoptosis and other cell death pathways indicate their critical roles in the genesis of DCM at the molecular level. The diabetic rats also showed cardiomyopathy with increased heart mass index, TNNI3K, troponin, etc. FeA effectively prevented the high glucose-induced MAM alterations and associated cellular anomalies both in vitro and in vivo. CONCLUSION: High glucose-induced MAM distortion and subsequent mitochondrial dysfunctions act as the stem of cardiomyopathy. MAM could be explored as a potential target to treat diabetic cardiomyopathy. Also, the FeA could be an attractive nutraceutical agent for diabetic cardiomyopathy. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Salin Raj, P AU - Salin Raj P AD - Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh 201002, India. FAU - Nair, Anupama AU - Nair A AD - Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh 201002, India. FAU - Preetha Rani, M R AU - Preetha Rani MR AD - Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh 201002, India. FAU - Rajankutty, K AU - Rajankutty K AD - Jubilee Centre for Medical Research (JCMR), Jubilee Mission Medical College and Research Institute, Thrissur, Kerala 680005, India. FAU - Ranjith, S AU - Ranjith S AD - Jubilee Centre for Medical Research (JCMR), Jubilee Mission Medical College and Research Institute, Thrissur, Kerala 680005, India. FAU - Raghu, K G AU - Raghu KG AD - Biochemistry and Molecular Mechanism Laboratory, Agro-Processing and Technology Division, CSIR - National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad, Uttar Pradesh 201002, India. Electronic address: raghukgopal2009@gmail.com. LA - eng PT - Journal Article DEP - 20221205 PL - Netherlands TA - Int J Cardiol JT - International journal of cardiology JID - 8200291 RN - 0 (Apoptosis Regulatory Proteins) RN - AVM951ZWST (ferulic acid) RN - 0 (FUNDC1 protein, rat) RN - IY9XDZ35W2 (Glucose) RN - 0 (Membrane Proteins) RN - 0 (Mitochondrial Proteins) RN - 0 (Pacs2 protein, rat) RN - 0 (Vdac1 protein, rat) RN - 0 (Vesicular Transport Proteins) RN - EC 1.6.- (Voltage-Dependent Anion Channel 1) SB - IM MH - Animals MH - Rats MH - Apoptosis MH - Apoptosis Regulatory Proteins/metabolism/pharmacology/therapeutic use MH - *Diabetes Mellitus, Experimental/metabolism MH - *Diabetic Cardiomyopathies/drug therapy/metabolism MH - Glucose/toxicity/metabolism MH - Membrane Proteins MH - Mitochondrial Proteins/pharmacology MH - Myocytes, Cardiac/metabolism MH - Vesicular Transport Proteins/metabolism MH - Voltage-Dependent Anion Channel 1/metabolism/therapeutic use MH - Mitochondria/metabolism MH - Endoplasmic Reticulum/metabolism OTO - NOTNLM OT - Apoptosis OT - Diabetic cardiomyopathy OT - Ferulic acid OT - MAM OT - Mitochondrial dynamics OT - OxPhos COIS- Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication among authors and there has been no significant financial support for this work that could have influenced its outcome. EDAT- 2022/12/09 06:00 MHDA- 2023/01/04 06:00 CRDT- 2022/12/08 23:27 PHST- 2022/09/02 00:00 [received] PHST- 2022/11/10 00:00 [revised] PHST- 2022/12/01 00:00 [accepted] PHST- 2022/12/09 06:00 [pubmed] PHST- 2023/01/04 06:00 [medline] PHST- 2022/12/08 23:27 [entrez] AID - S0167-5273(22)01873-3 [pii] AID - 10.1016/j.ijcard.2022.12.003 [doi] PST - ppublish SO - Int J Cardiol. 2023 Feb 1;372:101-109. doi: 10.1016/j.ijcard.2022.12.003. Epub 2022 Dec 5.