PMID- 31694459 OWN - NLM STAT- MEDLINE DCOM- 20200727 LR - 20210512 IS - 1524-4571 (Electronic) IS - 0009-7330 (Linking) VI - 126 IP - 2 DP - 2020 Jan 17 TI - miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders. PG - 212-228 LID - 10.1161/CIRCRESAHA.119.315067 [doi] AB - RATIONALE: Obstructive sleep apnea-hypopnea syndrome, a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown. OBJECTIVE: To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling. METHODS AND RESULTS: Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH before MI (CIH+MI) had no significant effect on post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathological remodeling and reduced survival rate. Mechanistically, CIH activated TGF-beta (tumor growth factor-beta)/Smad (homologs of both the Drosophila protein MAD and the C. elegans protein SMA) signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Real-time polymerase chain reaction/Western analysis confirmed that cardiomyocyte CTRP9 expression was significantly reduced in MI+CIH mice. RNA-sequencing, real-time polymerase chain reaction, and dual-luciferase reporter assays identified that microRNA-214-3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9 (adeno-associated virus 9)-mediated cardiac-specific CTRP9 overexpression or rCTRP9 (recombinated CTRP9) administration inhibited TGF-beta/Smad and Wnt/beta-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals. CONCLUSIONS: This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 (C1q tumor necrosis factor-related protein-9) expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathological remodeling in MI patients with obstructive sleep apnea-hypopnea syndrome. FAU - Du, Yunhui AU - Du Y AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Wang, Xiao AU - Wang X AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Li, Linyi AU - Li L AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Hao, Wenjing AU - Hao W AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Zhang, Huina AU - Zhang H AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Li, Yu AU - Li Y AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Qin, Yanwen AU - Qin Y AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Nie, Shaoping AU - Nie S AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). FAU - Christopher, Theodore A AU - Christopher TA AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Lopez, Bernard L AU - Lopez BL AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Lau, Wayne Bond AU - Lau WB AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Wang, Yajing AU - Wang Y AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Ma, Xin-Liang AU - Ma XL AD - Department of Emergency Medicine, Thomas Jefferson University, PA (Y.D., T.A.C., B.L.L., W.B.L., Y.W., X.-L.M.). FAU - Wei, Yongxiang AU - Wei Y AD - From the Beijing Key Laboratory of Upper Airway Dysfunction-Related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China (Y.D., X.W., L.L., W.H., H.Z., Y.L., Y.Q., S.N., Y.W.). LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191107 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Adiponectin) RN - 0 (CTRP9 protein, mouse) RN - 0 (Glycoproteins) RN - 0 (MicroRNAs) RN - 0 (Mirn214 microRNA, mouse) RN - 0 (Smad Proteins) RN - 0 (Transforming Growth Factor beta) SB - IM CIN - Circ Res. 2020 Jan 17;126(2):229-231. PMID: 31944919 CIN - Circ Res. 2020 Jun 5;126(12):e138-e139. PMID: 32496913 CIN - Circ Res. 2020 Jun 5;126(12):e136-e137. PMID: 32496916 MH - Adiponectin/genetics/*metabolism MH - Animals MH - Epithelial-Mesenchymal Transition MH - Glycoproteins/genetics/*metabolism MH - Humans MH - Hypoxia/complications/genetics/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - MicroRNAs/genetics/*metabolism MH - Myocardial Infarction/complications/*metabolism MH - Myocardium/metabolism/pathology MH - Sleep Apnea, Obstructive/complications/genetics/*metabolism MH - Smad Proteins/metabolism MH - Transcriptome MH - Transforming Growth Factor beta/metabolism MH - Ventricular Remodeling MH - Wnt Signaling Pathway OTO - NOTNLM OT - cardiokines OT - fibrosis OT - heart failure OT - hypoxia OT - sleep apnea EDAT- 2019/11/07 06:00 MHDA- 2020/07/28 06:00 CRDT- 2019/11/08 06:00 PHST- 2019/11/07 06:00 [pubmed] PHST- 2020/07/28 06:00 [medline] PHST- 2019/11/08 06:00 [entrez] AID - 10.1161/CIRCRESAHA.119.315067 [doi] PST - ppublish SO - Circ Res. 2020 Jan 17;126(2):212-228. doi: 10.1161/CIRCRESAHA.119.315067. Epub 2019 Nov 7.