title: Protein kinase D3 is a pivotal activator of pathological cardiac hypertrophy by selectively increasing the expression of hypertrophic transcription factors.
abstract: Fetal cardiac gene reactivation is a hallmark of pathological cardiac hypertrophy (PCH) driven by cardiac transcription factors (TFs) such as nuclear factor of activated T-cells (NFATs). Nuclear import of dephosphorylated NFATs catalyzed by calcineurin (CaN) is a well-established hypertrophic mechanism. Here we report that NFATc4 expression is also up-regulated by newly expressed protein kinase D3 (PKD3) to induce PCH. In both in vitro and in vivo cardiac hypertrophic models, the normally undetectable PKD3 was profoundly up-regulated by isoproterenol followed by overt expression of cardiac TFs including NFATc4, NK family of transcription factor 2.5 (Nkx2.5), GATA4 and myocyte enhancer factor 2 (MEF2). Using gene silencing approaches, we demonstrate PKD3 is required for increasing the expression of NFATc4, Nkx2.5, and GATA4 while PKD1 is required for the increase in MEF2D expression. Upstream induction of PKD3 is driven by nuclear entry of CaN-activated NFATc1 and c3 but not c4. Therefore, PKD3 is a pivotal mediator of the CaN-NFATc1/c3-PKD3-NFATc4 hypertrophic signaling cascade and a potential new drug target for the PCH.
authors.affiliation: Department of Pharmacology, Nankai University School of Medicine, Nankai, Tianjin 300071, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Cai
authors.forename: Haili
authors.initials: H
authors.lastname: Sun
authors.forename: Jinjin
authors.initials: J
authors.lastname: Jiao
authors.forename: Ting
authors.initials: T
authors.lastname: Bai
authors.forename: Xing Wang
authors.initials: XW
authors.lastname: Zhou
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gill
authors.forename: Xiang D
authors.initials: XD
authors.lastname: Tang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014157:Transcription Factors; D011494:Protein Kinases; C119190:protein kinase C nu; C089212:protein kinase D; D011493:Protein Kinase C; D007545:Isoproterenol