title: Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.
abstract: In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612, IL, United States of America.
authors.forename: Keven R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, United States of America.
authors.forename: Jessie
authors.initials: J
authors.lastname: Nicodemus-Johnson
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA, 94158, United States of America.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Spindler
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612, IL, United States of America.
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Carnegie
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D054758:A Kinase Anchor Proteins; C526201:Akap13 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; C089212:protein kinase D; D011493:Protein Kinase C