PMID- 33809417 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210413 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 3 DP - 2021 Mar 16 TI - Garcinol Attenuates Lipoprotein(a)-Induced Oxidative Stress and Inflammatory Cytokine Production in Ventricular Cardiomyocyte through alpha7-Nicotinic Acetylcholine Receptor-Mediated Inhibition of the p38 MAPK and NF-kappaB Signaling Pathways. LID - 10.3390/antiox10030461 [doi] LID - 461 AB - Garcinol, a nicotinic acetylcholine receptor (nAChR) antagonist, has recently been established as an anti-inflammation agent. However, the molecular mechanism by which garcinol suppresses inflammation in the context of acute myocardial infarction (AMI) remains unclear. Hypothesis: We hypothesized that the administration of physiological doses of garcinol in mice with isoproterenol-induced AMI decreased the effect of lipoprotein(a) (Lp(a))-induced inflammation both in vivo and in vitro via the alpha7-nAChRs mediated p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway. We analyzed altered reactive oxygen species (ROS) generation, the production of superoxide by mitochondria, cytokine expression patterns, and the role of the p38 MAPK/NF-kappaB signaling pathway after Lp(a)-stimulated human ventricular cardiomyocyte AC16 cells were treated with increasing doses of garcinol. C-reactive protein (CRP), interleukin (IL)-1beta, IL-6, or tumor necrosis factor (TNF)-alpha production were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 assay was used to evaluate drug cytotoxicity. Western blots and confocal fluorescence microscopy were used to determine altered expression patterns of inflammatory biomarkers. We also examined whether the therapeutic effect of garcinol in AMI was mediated in part by alpha7-nAChR. Lp(a)-induced inflammatory cardiomyocytes had increased expression of membrane-bound alpha7-nAChRs in vitro and in vivo. Low-dose garcinol did not affect cardiomyocyte viability but significantly reduced mitochondrial ROS, CRP, IL-1beta, IL-6, and TNF-alpha production in Lp(a)-stimulated cardiomyocytes (p < 0.05). The Lp(a)-induced phosphorylation of p38 MAPKs, CamKII, and NFkappaB, as well as NFkappaB-p65 nuclear translocation, was also suppressed (p < 0.05) by garcinol, while the inhibition of p38 MAPK by the inhibitor SB203580 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK. Garcinol protected cardiomyocytes by inhibiting apoptosis and inflammation in mice with AMI. Furthermore, garcinol also enhanced the expression of microRNA-205 that suppressed the alpha7-nAChR-induced p38 MAPK/NF-kappaB signaling pathway. Garcinol suppresses Lp(a)-induced oxidative stress and inflammatory cytokines by alpha7-nAChR-mediated inhibition of p38 MAPK/NF-kappaB signaling in cardiomyocyte AC16 cells and isoproterenol-induced AMI mice. FAU - Chang, Nen-Chung AU - Chang NC AD - Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan. AD - Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. AD - Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan. FAU - Yeh, Chi-Tai AU - Yeh CT AUID- ORCID: 0000-0001-5189-9755 AD - Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan. AD - Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan. FAU - Lin, Yen-Kuang AU - Lin YK AUID- ORCID: 0000-0002-7027-9508 AD - Biostatistics Center, Office of Data Science, Taipei Medical University, Taipei 110, Taiwan. AD - Graduate Institute of Data Science, Taipei Medical University, Taipei 110, Taiwan. AD - Research Center of Big Data, College of Management, Taipei Medical University, Taipei 110, Taiwan. FAU - Kuo, Kuang-Tai AU - Kuo KT AD - Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan. AD - Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Fong, Iat-Hang AU - Fong IH AD - Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan. AD - Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan. FAU - Kounis, Nicholas G AU - Kounis NG AUID- ORCID: 0000-0002-9751-6710 AD - Department of Internal Medicine, Division of Cardiology, University of Patras Medical School, 26221 Patras, Greece. FAU - Hu, Patrick AU - Hu P AD - Department of Cardiology, University of California, Riverside, CA 92521, USA. AD - Department of Cardiology, Riverside Medical Clinic, Riverside, CA 92506, USA. FAU - Hung, Ming-Yow AU - Hung MY AUID- ORCID: 0000-0002-6912-7523 AD - Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. AD - Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan. AD - Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan. LA - eng GR - MOST-108-2314-B-038-119-MY3/Ministry of Science and Technology, Taiwan/ PT - Journal Article DEP - 20210316 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC8000018 OTO - NOTNLM OT - NF-kappaB signaling OT - garcinol OT - nicotinic receptor OT - alpha7-nAChR COIS- The authors declare that they have no potential financial competing interests that may in any way, gain or lose financially from the publication of this manuscript at present or in the future. Additionally, no non-financial competing interests are involved in the manuscript. EDAT- 2021/04/04 06:00 MHDA- 2021/04/04 06:01 PMCR- 2021/03/16 CRDT- 2021/04/03 01:33 PHST- 2021/01/28 00:00 [received] PHST- 2021/02/27 00:00 [revised] PHST- 2021/03/10 00:00 [accepted] PHST- 2021/04/03 01:33 [entrez] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/04/04 06:01 [medline] PHST- 2021/03/16 00:00 [pmc-release] AID - antiox10030461 [pii] AID - antioxidants-10-00461 [pii] AID - 10.3390/antiox10030461 [doi] PST - epublish SO - Antioxidants (Basel). 2021 Mar 16;10(3):461. doi: 10.3390/antiox10030461.