{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T19:58:07Z","timestamp":1768939087015,"version":"3.49.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T00:00:00Z","timestamp":1454025600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T00:00:00Z","timestamp":1454025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>in vivo<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1038\/srep20024","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T11:07:29Z","timestamp":1454065649000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy"],"prefix":"10.1038","volume":"6","author":[{"given":"Buqing","family":"Cao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiping","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binhai","family":"Cong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiankui","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianqiang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,1,29]]},"reference":[{"key":"BFsrep20024_CR1","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1007\/s00018-008-8024-3","volume":"65","author":"A Lundwall","year":"2008","unstructured":"Lundwall, A. & Brattsand, M. Kallikrein-related peptidases. Cell Mol Life Sci. 65, 2019\u20132038 (2008).","journal-title":"Cell Mol Life Sci."},{"key":"BFsrep20024_CR2","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1515\/bc.2010.042","volume":"391","author":"J Chao","year":"2010","unstructured":"Chao, J. et al. Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing. Biol Chem. 391, 345\u2013355 (2010).","journal-title":"Biol Chem."},{"key":"BFsrep20024_CR3","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1097\/00004872-200404000-00017","volume":"22","author":"S Bergaya","year":"2004","unstructured":"Bergaya, S., Matrougui, K., Meneton, P., Henrion, D. & Boulanger, C. M. Role of tissue kallikrein in response to flow in mouse resistance arteries. J Hypertens. 22, 745\u2013750 (2004).","journal-title":"J Hypertens."},{"key":"BFsrep20024_CR4","first-page":"95","volume":"20","author":"A Akbar","year":"1998","unstructured":"Akbar, A., Sharma, J. N., Yusof, A. P. & Gan, E. K. Potentiation of bradykinin-induced responses by indomethacin in the intact and denuded epithelium of guinea pig tracheal preparations. Int J Tissue React. 20, 95\u2013100 (1998).","journal-title":"Int J Tissue React."},{"key":"BFsrep20024_CR5","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1515\/hsz-2012-0126","volume":"393","author":"SS Andrade","year":"2012","unstructured":"Andrade, S. S. et al. A plant Kunitz-type inhibitor mimics bradykinin-induced cytosolic calcium increase and intestinal smooth muscle contraction. Biol Chem. 393, 943\u2013957 (2012).","journal-title":"Biol Chem."},{"key":"BFsrep20024_CR6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1002\/ibd.21337","volume":"17","author":"A Stadnicki","year":"2011","unstructured":"Stadnicki, A. Intestinal tissue kallikrein-kinin system in inflammatory bowel disease. Inflamm Bowel Dis. 17, 645\u2013654 (2011).","journal-title":"Inflamm Bowel Dis."},{"key":"BFsrep20024_CR7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2174\/156720511794604570","volume":"8","author":"TA Viel","year":"2011","unstructured":"Viel, T. A. & Buck, H. S. Kallikrein-kinin system mediated inflammation in Alzheimer\u2019s disease in vivo. Curr Alzheimer Res. 8, 59\u201366 (2011).","journal-title":"Curr Alzheimer Res."},{"key":"BFsrep20024_CR8","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1515\/BC.2006.091","volume":"387","author":"T Kishi","year":"2006","unstructured":"Kishi, T., Cloutier, S. M., K\u00fcndig, C., Deperthes, D. & Diamandis, E. P. Activation and enzymatic characterization of recombinant human kallikrein 8. Biol Chem. 387, 723\u2013731 (2006).","journal-title":"Biol Chem."},{"key":"BFsrep20024_CR9","doi-asserted-by":"crossref","first-page":"6879","DOI":"10.1016\/j.febslet.2005.11.039","volume":"579","author":"S Rajapakse","year":"2005","unstructured":"Rajapakse, S., Ogiwara, K., Takano, N., Moriyama, A. & Takahashi, T. Biochemical characterization of human kallikrein 8 and its possible involvement in the degradation of extracellular matrix proteins. FEBS Lett. 579, 6879\u20136884 (2005).","journal-title":"FEBS Lett."},{"key":"BFsrep20024_CR10","doi-asserted-by":"crossref","first-page":"21606","DOI":"10.1074\/jbc.M309950200","volume":"279","author":"SM Casalino-Matsuda","year":"2004","unstructured":"Casalino-Matsuda, S. M., Monzon, M. E., Conner, G. E., Salathe, M. & Forteza, R. M. Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated epidermal growth factor receptor activation in human airways. J Biol Chem 279, 21606\u201321616 (2004).","journal-title":"J Biol Chem"},{"key":"BFsrep20024_CR11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1111\/j.1471-4159.2008.05658.x","volume":"107","author":"AG Vandell","year":"2008","unstructured":"Vandell, A. G. et al. Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J Neurochem. 107, 855\u2013870 (2008).","journal-title":"J Neurochem."},{"key":"BFsrep20024_CR12","doi-asserted-by":"crossref","first-page":"12293","DOI":"10.1074\/jbc.M709493200","volume":"283","author":"AJ Ramsay","year":"2008","unstructured":"Ramsay, A. J. et al. Hooper JD. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J Biol Chem. 283, 12293\u201312304 (2008).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR13","doi-asserted-by":"crossref","first-page":"5088","DOI":"10.1523\/JNEUROSCI.15-07-05088.1995","volume":"15","author":"ZL Chen","year":"1995","unstructured":"Chen, Z. L. et al. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J Neurosci. 15, 5088\u20135097 (1995).","journal-title":"J Neurosci."},{"key":"BFsrep20024_CR14","first-page":"375","volume":"391","author":"SKlk8 Yoshida","year":"2010","unstructured":"Yoshida, S. Klk8, a multifunctional protease in the brain and skin: analysis of knockout mice. Biol Chem. 391, 375\u2013380 (2010).","journal-title":"Biol Chem."},{"key":"BFsrep20024_CR15","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1074\/jbc.M607998200","volume":"282","author":"M Kishibe","year":"2007","unstructured":"Kishibe, M. et al. Kallikrein 8 is involved in skin desquamation in cooperation with other kallikreins. J Biol Chem. 282, 5834\u20135841 (2007).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jchemneu.2011.05.014","volume":"42","author":"S Shiosaka","year":"2011","unstructured":"Shiosaka, S. & Ishikawa, Y. Neuropsin\u2013a possible modulator of synaptic plasticity. J Chem Neuroanat. 42, 24\u201329 (2011).","journal-title":"J Chem Neuroanat."},{"key":"BFsrep20024_CR17","doi-asserted-by":"crossref","first-page":"11763","DOI":"10.1158\/0008-5472.CAN-06-3165","volume":"66","author":"YP Sher","year":"2006","unstructured":"Sher, Y. P. et al. Human kallikrein 8 protease confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness. Cancer Res. 66, 11763\u201311770 (2006).","journal-title":"Cancer Res."},{"key":"BFsrep20024_CR18","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/S0895-7061(99)00073-4","volume":"12","author":"C Emanueli","year":"1999","unstructured":"Emanueli, C. & Madeddu, P. Role of the kallikrein-kinin system in the maturation of cardiovascular phenotype. Am J Hypertens. 12, 988\u2013999 (1999).","journal-title":"Am J Hypertens."},{"key":"BFsrep20024_CR19","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1161\/01.HYP.0000021747.43346.95","volume":"40","author":"F Trabold","year":"2002","unstructured":"Trabold, F. et al. Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice. Hypertension. 40, 90\u201395 (2002).","journal-title":"Hypertension."},{"key":"BFsrep20024_CR20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1161\/01.HYP.35.1.25","volume":"35","author":"H Yoshida","year":"2000","unstructured":"Yoshida, H., Zhang, J. J., Chao, L. & Chao, J. Kallikrein gene delivery attenuates myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Hypertension. 35, 25\u201331 (2000).","journal-title":"Hypertension."},{"key":"BFsrep20024_CR21","doi-asserted-by":"crossref","first-page":"8022","DOI":"10.1074\/jbc.M407179200","volume":"280","author":"H Yin","year":"2005","unstructured":"Yin, H., Chao, L. & Chao, J. Kallikrein\/kinin protects against myocardial apoptosis after ischemia\/reperfusion via Akt-glycogen synthase kinase-3 and Akt-Bad.14-3-3 signaling pathways. J Biol Chem. 280, 8022\u20138030 (2005).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR22","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.lfs.2007.10.021","volume":"82","author":"H Yin","year":"2008","unstructured":"Yin, H., Chao, L. & Chao, J. Nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia\/reperfusion. Life Sci 82, 156\u2013165 (2008).","journal-title":"Life Sci"},{"key":"BFsrep20024_CR23","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1254\/jphs.SRJ05001X","volume":"99","author":"ME Moreau","year":"2005","unstructured":"Moreau, M. E. et al. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 99, 6\u201338 (2005).","journal-title":"J Pharmacol Sci."},{"key":"BFsrep20024_CR24","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1124\/jpet.104.077057","volume":"312","author":"S Purdom","year":"2005","unstructured":"Purdom, S. & Chen, Q. M. Epidermal growth factor receptor-dependent and \u2013independent pathways in hydrogen peroxide-induced mitogen-activated protein kinase activation in cardiomyocytes and heart fibroblasts. J Pharmacol Exp Ther 312, 1179\u20131186 (2005).","journal-title":"J Pharmacol Exp Ther"},{"key":"BFsrep20024_CR25","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1006\/jmcc.2000.1103","volume":"32","author":"MC Rebsamen","year":"2000","unstructured":"Rebsamen, M. C., Arrighi, J. F., Juge-Aubry, C. E., Vallotton, M. B. & Lang, U. Epidermal growth factor induces hypertrophic responses and Stat5 activation in rat ventricular cardiomyocytes. J Mol Cell Cardiol. 32, 599\u2013610 (2000).","journal-title":"J Mol Cell Cardiol."},{"key":"BFsrep20024_CR26","doi-asserted-by":"crossref","first-page":"e81733","DOI":"10.1371\/journal.pone.0081733","volume":"8","author":"S Antoniak","year":"2013","unstructured":"Antoniak, S., Sparkenbaugh, E. M., Tencati, M., Rojas, M., Mackman, N. & Pawlinski, R. Protease activated receptor-2 contributes to heart failure. PLoS One. 8, e81733 (2013).","journal-title":"PLoS One."},{"key":"BFsrep20024_CR27","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1161\/CIRCULATIONAHA.107.692764","volume":"116","author":"R Pawlinski","year":"2007","unstructured":"Pawlinski, R. et al. Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation. 116, 2298\u20132306 (2007).","journal-title":"Circulation."},{"key":"BFsrep20024_CR28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1124\/mol.104.003103","volume":"67","author":"SF Steinberg","year":"2005","unstructured":"Steinberg, S. F. The cardiovascular actions of protease-activated receptors. Mol Pharmacol. 67, 2\u201311 (2005).","journal-title":"Mol Pharmacol."},{"key":"BFsrep20024_CR29","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.tem.2004.06.011","volume":"15","author":"BH Shah","year":"2004","unstructured":"Shah, B. H. & Catt, K. J. Matrix metalloproteinase-dependent EGF receptor activation in hypertension and left ventricular hypertrophy. Trends Endocrinol Metab. 15, 241\u2013243 (2004).","journal-title":"Trends Endocrinol Metab."},{"key":"BFsrep20024_CR30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.yjmcc.2014.06.018","volume":"75","author":"H Huang","year":"2014","unstructured":"Huang, H., Joseph, L. C., Gurin, M. I., Thorp, E. B. & Morrow, J. P. Extracellular signal-regulated kinase activation during cardiac hypertrophy reduces sarcoplasmic\/endoplasmic reticulum calcium ATPase 2 (SERCA2) transcription. J Mol Cell Cardiol. 75, 58\u201363 (2014).","journal-title":"J Mol Cell Cardiol."},{"key":"BFsrep20024_CR31","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.intimp.2007.08.029","volume":"8","author":"EC Batista","year":"2008","unstructured":"Batista, E. C. et al. Swimming training exacerbates pathological cardiac hypertrophy in kinin B2 receptor-deficient mice. Int Immunopharmacol 8, 271\u2013275 (2008).","journal-title":"Int Immunopharmacol"},{"key":"BFsrep20024_CR32","doi-asserted-by":"crossref","first-page":"H1479","DOI":"10.1152\/ajpheart.01129.2002","volume":"285","author":"G Bledsoe","year":"2003","unstructured":"Bledsoe, G., Chao, L. & Chao, J. Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 285, H1479\u2013H1488 (2003).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep20024_CR33","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1089\/hum.1998.9.1-21","volume":"9","author":"J Chao","year":"1998","unstructured":"Chao, J., Zhang, J. J., Lin, K. F. & Chao, L. Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy and renal injury in Dahl salt-sensitive rats. Hum Gene Ther. 9, 21\u201331 (1998).","journal-title":"Hum Gene Ther."},{"key":"BFsrep20024_CR34","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.cardiores.2006.10.014","volume":"73","author":"HJ Li","year":"2007","unstructured":"Li, H. J. et al. Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3beta activation. Cardiovasc Res. 73, 130\u2013142 (2007).","journal-title":"Cardiovasc Res."},{"key":"BFsrep20024_CR35","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1096\/fj.99-1010fje","volume":"14","author":"JA Silva Jr.","year":"2000","unstructured":"Silva, J. A. Jr. et al. Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 14, 1858\u20131860 (2000).","journal-title":"FASEB J"},{"key":"BFsrep20024_CR36","doi-asserted-by":"crossref","first-page":"H116","DOI":"10.1152\/ajpheart.2000.279.1.H116","volume":"279","author":"HL Pan","year":"2000","unstructured":"Pan, H. L., Chen, S. R., Scicli, G. M. & Carretero, O. A. Cardiac interstitial bradykinin release during ischemia is enhanced by ischemic preconditioning. Am J Physiol Heart Circ Physiol 279, H116\u2013H121 (2000).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep20024_CR37","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.arcmed.2005.08.001","volume":"37","author":"JN Sharma","year":"2006","unstructured":"Sharma, J. N. Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system. Arch Med Res. 37, 299\u2013306 (2006).","journal-title":"Arch Med Res."},{"key":"BFsrep20024_CR38","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/ki.2008.647","volume":"75","author":"M Kakoki","year":"2009","unstructured":"Kakoki, M. & Smithies, O. The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int 75, 1019\u20131030 (2009).","journal-title":"Kidney Int"},{"key":"BFsrep20024_CR39","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1161\/HYPERTENSIONAHA.108.114587","volume":"52","author":"J Chao","year":"2008","unstructured":"Chao, J. et al. Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. Hypertension. 52, 715\u2013720 (2008).","journal-title":"Hypertension."},{"key":"BFsrep20024_CR40","doi-asserted-by":"crossref","first-page":"25505","DOI":"10.1074\/jbc.M110.213231","volume":"286","author":"A Guillon-Munos","year":"2011","unstructured":"Guillon-Munos, A. Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors. J Biol Chem. 286, 25505\u201325518 (2011).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR41","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1210\/en.2012-1011","volume":"153","author":"WY Sanchez","year":"2012","unstructured":"Sanchez, W. Y. Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells. Endocrinology. 153, 3179\u20133189 (2012).","journal-title":"Endocrinology."},{"key":"BFsrep20024_CR42","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1074\/jbc.M110.125310","volume":"286","author":"A Eissa","year":"2011","unstructured":"Eissa, A., Amodeo, V., Smith, C. R. & Diamandis, E. P. Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade. J Biol Chem. 286, 687\u2013706 (2011).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR43","first-page":"22","volume":"1776","author":"G Pampalakis","year":"2007","unstructured":"Pampalakis, G. & Sotiropoulou, G. Tissue kallikrein proteolytic cascade pathways in normal physiology and cancer. Biochim Biophys Acta. 1776, 22\u201331 (2007).","journal-title":"Biochim Biophys Acta."},{"key":"BFsrep20024_CR44","doi-asserted-by":"crossref","first-page":"35206","DOI":"10.1074\/jbc.M110.171769","volume":"285","author":"RT Abdallah","year":"2010","unstructured":"Abdallah, R. T. et al. Plasma kallikrein promotes epidermal growth factor receptor transactivation and signaling in vascular smooth muscle through direct activation of protease-activated receptors. J Biol Chem. 285, 35206\u201335215 (2010).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1124\/mol.104.003103","volume":"67","author":"SF Steinberg","year":"2005","unstructured":"Steinberg, S. F. The cardiovascular actions of protease-activated receptors. Mol Pharmacol. 67, 2\u201311 (2005).","journal-title":"Mol Pharmacol."},{"key":"BFsrep20024_CR46","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1161\/01.RES.86.10.1054","volume":"86","author":"A Sabri","year":"2000","unstructured":"Sabri, A. et al. Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res. 86, 1054\u20131061 (2000).","journal-title":"Circ Res."},{"key":"BFsrep20024_CR47","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.2353\/ajpath.2010.090523","volume":"176","author":"V Gratio","year":"2010","unstructured":"Gratio, V. et al. Kallikrein-related peptidase 4: a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol. 176, 1452\u20131461 (2010).","journal-title":"Am J Pathol."},{"key":"BFsrep20024_CR48","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1016\/j.ajpath.2011.07.016","volume":"179","author":"V Gratio","year":"2011","unstructured":"Gratio, V. et al. Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. Am J Pathol. 179, 2625\u20132636 (2011).","journal-title":"Am J Pathol."},{"key":"BFsrep20024_CR49","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1111\/j.1471-4159.2008.05658.x","volume":"107","author":"AG Vandell","year":"2008","unstructured":"Vandell, A. G. et al. Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines. J Neurochem. 107, 855\u2013870 (2008).","journal-title":"J Neurochem."},{"key":"BFsrep20024_CR50","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ijcard.2005.11.106","volume":"112","author":"A Phrommintikul","year":"2006","unstructured":"Phrommintikul, A. & Chattipakorn, N. Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. Int J Cardiol. 112, 142\u2013152 (2006).","journal-title":"Int J Cardiol."},{"key":"BFsrep20024_CR51","doi-asserted-by":"crossref","first-page":"7425","DOI":"10.1038\/srep07425","volume":"4","author":"Q Yuan","year":"2014","unstructured":"Yuan, Q. et al. Functional role of Calstabin2 in age-related cardiac alterations. Sci Rep. 4, 7425 (2014).","journal-title":"Sci Rep"},{"key":"BFsrep20024_CR52","doi-asserted-by":"crossref","first-page":"10844","DOI":"10.1021\/bi2013855","volume":"50","author":"S Mathea","year":"2011","unstructured":"Mathea, S., Li, S., Schierhorn, A., Jahreis, G. & Schiene-Fischer, C. Suppression of EGFR autophosphorylation by FKBP12. Biochemistry. 50, 10844\u201310850 (2011).","journal-title":"Biochemistry."},{"key":"BFsrep20024_CR53","doi-asserted-by":"crossref","first-page":"a025148","DOI":"10.1101\/cshperspect.a025148","volume":"5","author":"YA Chiao","year":"2015","unstructured":"Chiao, Y. A. & Rabinovitch, P. S. The Aging Heart. Cold Spring Harb Perspect Med. 5, a025148 (2015).","journal-title":"Cold Spring Harb Perspect Med."},{"key":"BFsrep20024_CR54","doi-asserted-by":"crossref","first-page":"338","DOI":"10.12965\/jer.130049","volume":"9","author":"HB Kwak","year":"2013","unstructured":"Kwak, H. B. Aging, exercise and extracellular matrix in the heart. J Exerc Rehabil. 9, 338\u2013347 (2013).","journal-title":"J Exerc Rehabil"},{"key":"BFsrep20024_CR55","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0188-0128(99)00059-7","volume":"30","author":"JA Garc\u00eda-S\u00e1inz","year":"1999","unstructured":"Garc\u00eda-S\u00e1inz, J. A., V\u00e1zquez-Prado, J. & Villalobos-Molina, R. Alpha 1-adrenoceptors: subtypes, signaling and roles in health and disease. Arch Med Res. 30, 449\u2013458 (1999).","journal-title":"Arch Med Res."},{"key":"BFsrep20024_CR56","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.1074\/jbc.M607567200","volume":"282","author":"CA Borgo\u00f1o","year":"2007","unstructured":"Borgo\u00f1o, C. A. et al. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 282, 3640\u20133652 (2007).","journal-title":"J Biol Chem"},{"key":"BFsrep20024_CR57","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1074\/jbc.M707253200","volume":"283","author":"N Emami","year":"2008","unstructured":"Emami, N. & Diamandis, E. P. Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade. Possible function in seminal plasma and skin. J Biol Chem. 283, 3031\u20133041 (2008).","journal-title":"J Biol Chem."},{"key":"BFsrep20024_CR58","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0167-5273(97)00329-X","volume":"63","author":"JN Sharma","year":"1998","unstructured":"Sharma, J. N., Uma, K. & Yusof, A. P. Left ventricular hypertrophy and its relation to the cardiac kinin-forming system in hypertensive and diabetic rats. Int J Cardiol. 63, 229\u2013235 (1998).","journal-title":"Int J Cardiol."},{"key":"BFsrep20024_CR59","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.clnu.2014.08.014","volume":"34","author":"YQ Zhang","year":"2015","unstructured":"Zhang, Y. Q. et al. Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-\u03b21 signaling. Clin Nutr. 34, 752\u2013760 (2015).","journal-title":"Clin Nutr."},{"key":"BFsrep20024_CR60","doi-asserted-by":"crossref","first-page":"e001081","DOI":"10.1161\/JAHA.112.001081","volume":"1","author":"G Santulli","year":"2012","unstructured":"Santulli, G. et al. CaMK4 Gene Deletion Induces Hypertension. J Am Heart Assoc. 1, e001081 (2012).","journal-title":"J Am Heart Assoc"},{"key":"BFsrep20024_CR61","first-page":"271","volume":"30","author":"SA Nicklin","year":"1999","unstructured":"Nicklin S. A. & Baker A. H. Simple methods for preparing recombinant adenoviruses for high-efficiency transduction of vascular cells. Methods Mol Med. 30, 271\u2013283 (1999).","journal-title":"Methods Mol Med."},{"key":"BFsrep20024_CR62","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1161\/CIRCULATIONAHA.108.803999","volume":"119","author":"G Rengo","year":"2009","unstructured":"Rengo, G. et al. Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation. 119, 89\u201398 (2009).","journal-title":"Circulation."},{"key":"BFsrep20024_CR63","doi-asserted-by":"crossref","first-page":"e104040","DOI":"10.1371\/journal.pone.0104040","volume":"9","author":"C Chen","year":"2014","unstructured":"Chen, C. et al. Cytosolic CARP promotes angiotensin II- or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation. PLoS One. 9, e104040 (2014).","journal-title":"PLoS One."},{"key":"BFsrep20024_CR64","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s00395-005-0521-z","volume":"100","author":"J Ma","year":"2005","unstructured":"Ma, J. et al. Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction. Basic Res Cardiol. 100, 217\u2013223 (2005).","journal-title":"Basic Res Cardiol."},{"key":"BFsrep20024_CR65","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ijcard.2011.01.029","volume":"148","author":"X Jian","year":"2011","unstructured":"Jian X. et al. MiR-204 regulate cardiomyocyte autophagy induced by hypoxia-reoxygenation through LC3-II. Int J Cardiol. 148, 110\u2013112 (2011).","journal-title":"Int J Cardiol."}],"updated-by":[{"DOI":"10.1038\/srep25038","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2016,4,29]],"date-time":"2016-04-29T00:00:00Z","timestamp":1461888000000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep20024.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep20024","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep20024.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T23:36:27Z","timestamp":1672875387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep20024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,29]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,22]]}},"alternative-id":["BFsrep20024"],"URL":"https:\/\/doi.org\/10.1038\/srep20024","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,29]]},"assertion":[{"value":"15 January 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2016","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20024"}}