PMID- 35941186 OWN - NLM STAT- MEDLINE DCOM- 20230113 LR - 20230707 IS - 1530-0307 (Electronic) IS - 0023-6837 (Print) IS - 0023-6837 (Linking) VI - 102 IP - 11 DP - 2022 Nov TI - Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice. PG - 1192-1202 LID - S0023-6837(22)00257-4 [pii] LID - 10.1038/s41374-022-00819-2 [doi] AB - Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 muL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice. CI - (c) 2022. The Author(s). FAU - Deng, Ya-Wen AU - Deng YW AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. FAU - Liu, Fei AU - Liu F AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. FAU - Li, Zhi-Tong AU - Li ZT AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. FAU - Gao, Jing-Han AU - Gao JH AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. FAU - Zhao, Yong AU - Zhao Y AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. FAU - Yang, Xiao-Lei AU - Yang XL AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. yangxl1012@yeah.net. FAU - Xia, Yun-Long AU - Xia YL AUID- ORCID: 0000-0001-7985-3273 AD - Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No.193, Lianhe Road, Xigang District, 116011, Dalian, China. dlmu_xiayunlong@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220808 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - 0 (4-phenylbutylamine) RN - 85637-73-6 (Atrial Natriuretic Factor) RN - 9007-34-5 (Collagen) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - 114471-18-0 (Natriuretic Peptide, Brain) RN - 0 (Receptors, Leptin) RN - 0 (RNA, Messenger) RN - EC 3.5.1.- (Sirtuin 1) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase 10) SB - IM EIN - Lab Invest. 2022 Aug 30;:. PMID: 36042280 MH - Animals MH - Mice MH - Atrial Natriuretic Factor MH - Cardiomegaly/etiology MH - *Cardiomyopathies/metabolism MH - Collagen MH - *Diabetes Mellitus, Experimental/complications MH - *Diabetes Mellitus, Type 2/complications/metabolism MH - Endoplasmic Reticulum Stress/physiology MH - Fibrosis MH - *Hyperglycemia/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Natriuretic Peptide, Brain MH - Receptors, Leptin/genetics MH - RNA, Messenger MH - Signal Transduction MH - Sirtuin 1/metabolism MH - Mitogen-Activated Protein Kinase 10/metabolism PMC - PMC9588458 COIS- The authors declare no competing interests. EDAT- 2022/08/09 06:00 MHDA- 2022/10/26 06:00 PMCR- 2022/08/08 CRDT- 2022/08/08 23:21 PHST- 2022/01/10 00:00 [received] PHST- 2022/06/15 00:00 [accepted] PHST- 2022/06/15 00:00 [revised] PHST- 2022/08/09 06:00 [pubmed] PHST- 2022/10/26 06:00 [medline] PHST- 2022/08/08 23:21 [entrez] PHST- 2022/08/08 00:00 [pmc-release] AID - S0023-6837(22)00257-4 [pii] AID - 819 [pii] AID - 10.1038/s41374-022-00819-2 [doi] PST - ppublish SO - Lab Invest. 2022 Nov;102(11):1192-1202. doi: 10.1038/s41374-022-00819-2. Epub 2022 Aug 8.