title: Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy.
abstract: The tissue kallikrein-related peptidase family (KLK) is a group of trypsin- and chymotrypsin-like serine proteases that share a similar homology to parent tissue kallikrein (KLK1). KLK1 is identified in heart and has anti-hypertrophic effects. However, whether other KLK family members play a role in regulating cardiac function remains unknown. In the present study, we demonstrated for the first time that KLK8 was expressed in myocardium. KLK8 expression was upregulated in left ventricle of cardiac hypertrophy models. Both intra-cardiac adenovirus-mediated and transgenic-mediated KLK8 overexpression led to cardiac hypertrophy in vivo. In primary neonatal rat cardiomyocytes, KLK8 knockdown inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas KLK8 overexpression promoted cardiomyocyte hypertrophy via a serine protease activity-dependent but kinin receptor-independent pathway. KLK8 overexpression increased epidermal growth factor (EGF) production, which was blocked by the inhibitors of serine protease. EGF receptor (EGFR) antagonist and EGFR knockdown reversed the hypertrophy induced by KLK8 overexpression. KLK8-induced cardiomyocyte hypertrophy was also significantly decreased by blocking the protease-activated receptor 1 (PAR1) or PAR2 pathway. Our data suggest that KLK8 may promote cardiomyocyte hypertrophy through EGF signaling- and PARs-dependent but a kinin receptor-independent pathway. It is implied that different KLK family members can subtly regulate cardiac function and remodeling.
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Buqing
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: School of Kinesiology, The key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Binhai
authors.initials: B
authors.lastname: Cong
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jiankui
authors.initials: J
authors.lastname: Du
authors.affiliation: School of Kinesiology, The key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Physiology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ni
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007610:Kallikreins / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D007610:Kallikreins; C485430:Klk8 protein, rat; D012697:Serine Endopeptidases
references.citation: Biochim Biophys Acta. 2007 Sep;1776(1):22-31
references.pmid: 17629406
references.citation: J Biol Chem. 2007 Feb 9;282(6):3640-52
references.pmid: 17158887
references.citation: Biol Chem. 2012 Sep;393(9):943-57
references.pmid: 22944694
references.citation: Am J Hypertens. 1999 Oct;12(10 Pt 1):988-99
references.pmid: 10560785
references.citation: J Biol Chem. 2011 Jan 7;286(1):687-706
references.pmid: 20940292
references.citation: Int J Cardiol. 2011 Apr 1;148(1):110-2
references.pmid: 21316776
references.citation: J Biol Chem. 2007 Feb 23;282(8):5834-41
references.pmid: 17182622
references.citation: Cancer Res. 2006 Dec 15;66(24):11763-70
references.pmid: 17178872
references.citation: Cell Mol Life Sci. 2008 Jul;65(13):2019-38
references.pmid: 18344018
references.citation: Int J Tissue React. 1998;20(3):95-100
references.pmid: 9894182
references.citation: Inflamm Bowel Dis. 2011 Feb;17(2):645-54
references.pmid: 20848521
references.citation: Hum Gene Ther. 1998 Jan 1;9(1):21-31
references.pmid: 9458239
references.citation: Cardiovasc Res. 2007 Jan 1;73(1):130-42
references.pmid: 17137568
references.citation: PLoS One. 2014;9(8):e104040
references.pmid: 25089522
references.citation: J Pharmacol Exp Ther. 2005 Mar;312(3):1179-86
references.pmid: 15574683
references.citation: Biol Chem. 2010 Apr;391(4):345-55
references.pmid: 20180644
references.citation: Int J Cardiol. 2006 Sep 20;112(2):142-52
references.pmid: 16701909
references.citation: FASEB J. 2000 Oct;14(13):1858-60
references.pmid: 11023967
references.citation: Circulation. 2007 Nov 13;116(20):2298-306
references.pmid: 17967980
references.citation: Circulation. 2009 Jan 6;119(1):89-98
references.pmid: 19103992
references.citation: Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H116-21
references.pmid: 10899048
references.citation: Methods Mol Med. 1999;30:271-83
references.pmid: 21341032
references.citation: Circ Res. 2000 May 26;86(10):1054-61
references.pmid: 10827135
references.citation: Endocrinology. 2012 Jul;153(7):3179-89
references.pmid: 22547569
references.citation: Biochemistry. 2011 Dec 20;50(50):10844-50
references.pmid: 22103444
references.citation: J Hypertens. 2004 Apr;22(4):745-50
references.pmid: 15126916
references.citation: Arch Med Res. 1999 Nov-Dec;30(6):449-58
references.pmid: 10714357
references.citation: Hypertension. 2000 Jan;35(1 Pt 1):25-31
references.pmid: 10642270
references.citation: J Biol Chem. 2005 Mar 4;280(9):8022-30
references.pmid: 15611141
references.citation: Sci Rep. 2014;4:7425
references.pmid: 25502776
references.citation: J Biol Chem. 2004 May 14;279(20):21606-16
references.pmid: 14988406
references.citation: PLoS One. 2013;8(11):e81733
references.pmid: 24312345
references.citation: Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1479-88
references.pmid: 12816755
references.citation: Am J Pathol. 2011 Nov;179(5):2625-36
references.pmid: 21907696
references.citation: J Mol Cell Cardiol. 2000 Apr;32(4):599-610
references.pmid: 10756117
references.citation: J Pharmacol Sci. 2005 Sep;99(1):6-38
references.pmid: 16177542
references.citation: J Biol Chem. 2008 May 2;283(18):12293-304
references.pmid: 18308730
references.citation: J Mol Cell Cardiol. 2014 Oct;75:58-63
references.pmid: 25008120
references.citation: Biol Chem. 2006 Jun;387(6):723-31
references.pmid: 16800733
references.citation: J Am Heart Assoc. 2012 Aug;1(4):e001081
references.pmid: 23130158
references.citation: Am J Pathol. 2010 Mar;176(3):1452-61
references.pmid: 20056842
references.citation: Clin Nutr. 2015 Aug;34(4):752-60
references.pmid: 25234611
references.citation: Basic Res Cardiol. 2005 May;100(3):217-23
references.pmid: 15754085
references.citation: J Neurochem. 2008 Nov;107(3):855-70
references.pmid: 18778305
references.citation: J Neurosci. 1995 Jul;15(7 Pt 2):5088-97
references.pmid: 7623137
references.citation: Hypertension. 2008 Oct;52(4):715-20
references.pmid: 18768400
references.citation: Mol Pharmacol. 2005 Jan;67(1):2-11
references.pmid: 15371558
references.citation: Hypertension. 2002 Jul;40(1):90-5
references.pmid: 12105144
references.citation: Int J Cardiol. 1998 Feb 28;63(3):229-35
references.pmid: 9578349
references.citation: Kidney Int. 2009 May;75(10):1019-30
references.pmid: 19190676
references.citation: Int Immunopharmacol. 2008 Feb;8(2):271-5
references.pmid: 18182239
references.citation: FEBS Lett. 2005 Dec 19;579(30):6879-84
references.pmid: 16337200
references.citation: Life Sci. 2008 Jan 16;82(3-4):156-65
references.pmid: 18068196
references.citation: J Biol Chem. 2010 Nov 5;285(45):35206-15
references.pmid: 20826789
references.citation: Arch Med Res. 2006 Apr;37(3):299-306
references.pmid: 16513476
references.citation: J Chem Neuroanat. 2011 Sep;42(1):24-9
references.pmid: 21679765
references.citation: J Biol Chem. 2008 Feb 8;283(6):3031-41
references.pmid: 18056261
references.citation: Biol Chem. 2010 Apr;391(4):375-80
references.pmid: 20180635
references.citation: Cold Spring Harb Perspect Med. 2015;5(9):a025148
references.pmid: 26328932
references.citation: Curr Alzheimer Res. 2011 Feb;8(1):59-66
references.pmid: 21143155
references.citation: J Biol Chem. 2011 Jul 22;286(29):25505-18
references.pmid: 21628462
references.citation: J Exerc Rehabil. 2013 Jun 30;9(3):338-47
references.pmid: 24278882
references.citation: Trends Endocrinol Metab. 2004 Aug;15(6):241-3
references.pmid: 15358274