title: C1q-TNF-related protein-9, a novel cardioprotetcive cardiokine, requires proteolytic cleavage to generate a biologically active globular domain isoform.
abstract: Prevalence and severity of postmyocardial infarction heart failure continually escalate in type 2 diabetes via incompletely understood mechanisms. The discovery of the cardiac secretomes, collectively known as "cardiokines", has significantly enhanced appreciation of the local microenvironment's influence on disease development. Recent studies demonstrated that C1q-TNF-related protein-9 (CTRP9), a newly discovered adiponectin (APN) paralog, is highly expressed in the heart. However, its relationship with APN (concerning diabetic cardiovascular injury in particular) remains unknown. Plasma CTRP9 levels are elevated in APN knockout and reduced in diabetic mice. In contrast to APN, which circulates as full-length multimers, CTRP9 circulates in the plasma primarily in the globular domain isoform (gCTRP9). Recombinant full-length CTRP9 (fCTRP9) was cleaved when incubated with cardiac tissue extracts, generating gCTRP9, a process inhibited by protease inhibitor cocktail. gCTRP9 rapidly activates cardiac survival kinases, including AMPK, Akt, and endothelial NOS. However, fCTRP9-mediated kinase activation is much less potent and significantly delayed. Kinase activation by fCTRP9, but not gCTRP9, is inhibited by protease inhibitor cocktail. These results demonstrate for the first time that the novel cardiokine CTRP9 undergoes proteolytic cleavage to generate gCTRP9, the dominant circulatory and actively cardioprotective isoform. Enhancing cardiac CTRP9 production and/or its proteolytic posttranslational modification are of therapeutic potential, attenuating diabetic cardiac injury.
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Zhejiang Provincial Hospital of Chinese Traditional Medicine, Hangzhou, Zhejiang Province, China.
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania;
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.affiliation: Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, Xi'an, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, Xi'an, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania;
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, Xi'an, China;
authors.forename: Theodore
authors.initials: T
authors.lastname: Christopher
authors.affiliation: Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, Xi'an, China;
authors.forename: Bernard
authors.initials: B
authors.lastname: Lopez
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania;
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; and Xin.Ma@Jefferson.edu.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain / Q000235:genetics*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D059305:Diet, High-Fat; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D059748:Proteolysis
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; C534692:CTRP9 protein, mouse; D002316:Cardiotonic Agents; D006023:Glycoproteins; D020033:Protein Isoforms
keywords: CTRP9; adiponectin; cardiokine; diabetes; proteolysis