title: Let-7a regulates expression of β1-adrenoceptors and forms a negative feedback circuit with the β1-adrenoceptor signaling pathway in chronic ischemic heart failure.
abstract: BACKGROUND
  The aim of the present study was to investigate the role of microRNA (miRNA) let-7a in down-regulation of β1-adrenoceptors (β1-AR) and elucidate the underlying mechanism of chronic ischemia heart failure (CIHF) in rats.
  
  
  RESULTS
  CIHF model was established by occlusion of coronary artery for 4 weeks. β1-AR level was obviously down-regulated and let-7a up-regulated in the failing heart 4 weeks after myocardial infarction. Overexpression of let-7a inhibited β1-AR expression in neonatal rat ventricular cells (NRVCs), which was abolished by anti-let-7a antisense inhibitor. The lentivirus vector containing precursor let-7a (len-pre-let-7a) further down-regulated the reduced β1-AR level by CIHF and the effect was reversed by len-AMO-let-7a. Len-negative control did not produce any significant influence on β1-AR expression. Importantly, there exists a negative feedback loop associated with β1-AR regulation through β1-AR/cAMP/PKA/GATA4/let-7a/β1-AR signaling pathway in CIHF. As demonstrated, GATA4 was activated by β1-AR up-regulation through cAMP-PKA signaling pathway in early phase of ischemia, then GATA4 positively regulated let-7a expression which in turn suppressed β1-AR expression.
  
  
  CONCLUSIONS
  Let-7a regulates β1-AR expression and forms a negative feedback loop with β1-AR signaling pathway in ischemic heart failure. This study provides a new insight into the differential expression of β1-AR in early and later phase of myocardial ischemia.
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: You
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Ti
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.|Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D050991:GATA4 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C547789:Adrb1 protein, rat; D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D018342:Receptors, Adrenergic, beta-1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: GATA4; chronic ischemia heart failure; let-7a; β1-AR