Limits...
Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.

Johnson KR, Nicodemus-Johnson J, Spindler MJ, Carnegie GK - PLoS ONE (2015)

Bottom Line: Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612, IL, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Myofilament Gene expression stratified by WT or AKAP13-∆PKD1 mice following sham or TAC surgery.Normalized (log-transformed) gene expression is shown for myofilament proteins A) Desmin (Des), B) Myosin binding protein C-2 (MybpC2), C) Troponin T1 (Tnnt1), D) Myosin binding protein C-3, E) Popeye protein-3 (Popcd3), and F) Ankyrin repeat domain 23 (Ankrd23). Gray boxes represent the interquartile range, encompassing the first through third quartiles; the horizontal bar shows the median value. Values greater than 1.5 times the interquartile range are plotted outside of the whiskers. P values are from linear regression assuming an additive model.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4508115&req=5

pone.0132474.g008: Myofilament Gene expression stratified by WT or AKAP13-∆PKD1 mice following sham or TAC surgery.Normalized (log-transformed) gene expression is shown for myofilament proteins A) Desmin (Des), B) Myosin binding protein C-2 (MybpC2), C) Troponin T1 (Tnnt1), D) Myosin binding protein C-3, E) Popeye protein-3 (Popcd3), and F) Ankyrin repeat domain 23 (Ankrd23). Gray boxes represent the interquartile range, encompassing the first through third quartiles; the horizontal bar shows the median value. Values greater than 1.5 times the interquartile range are plotted outside of the whiskers. P values are from linear regression assuming an additive model.

Mentions: Select gene differential expression changes identified via microarray interrogation of WT and AKAP13-∆PKD1 hearts were sub-categorized into myofilament, apoptosis, cell growth/differentiation, energy metabolism, or oxidative stress–related molecules (Figs 8–12). Myofilament-Associated Genes: Significant differences between WT-sham/TAC and AKAP13-∆PKD1-Sham/TAC were seen in multiple myofilament genes (Fig 8). Desmin (Des), myosin binding protein C-2 (MybpC-2), troponin T-1 (Tnnt1), and myosin binding protein C-3 (MybpC3) were all significantly different between WT-Sham and WT-TAC hearts but not between AKAP13-∆PKD1-sham and TAC hearts. The cardiac muscle development-associated gene Popdc3 is elevated in both WT and AKAP13-∆PKD1 TAC hearts compared to sham, though at different significance level (Fig 8E). The stretch-induced transcription factor Ankrd23 is elevated in both WT-TAC and AKAP13-∆PKD1 TAC compared to sham hearts (Fig 8F). Apoptosis-Associated Genes: Significantly elevated apoptosis gene expression levels were identified in WT-TAC but not GT-TAC for Fadd and Bcl2 (Fig 9A and 9B). Expression levels for the genes Bax, Nudt1, and Gzmm are significantly reduced in WT-TAC but not AKAP13-∆PKD1 TAC compared to sham (Fig 9C–9E). Cell growth and differentiation-associated genes: Significantly elevated expression of Nuak1 was seen in WT-TAC but not GT-TAC (Fig 10A), while significantly reduced expression of Igf2 and Tgfβr3 was seen in WT-TAC but not AKAP13-∆PKD1 TAC (Fig 10B and 10C). Significantly elevated expression of both Tgfb3 and Emp1 are seen in WT-TAC and AKAP13-∆PKD1 TAC (Fig 10D and 10E). Metabolism-associated genes: Significant reduction in Etfb expression was found in WT-TAC but not AKAP13-∆PKD1 TAC hearts (Fig 11A). Several other energy metabolism-related genes were significantly altered in both WT-TAC and AKAP13-∆PKD1 TAC hearts, though at different significance levels (Fig 11B–11E). Oxidative stress response genes: Expression of the oxidative stress-response gene Sod1 was significantly reduced in WT-TAC hearts but not in AKAP13-∆PKD1 TAC hearts (Fig 12A). Other oxidative stress-response genes had similar expression profiles for WT-TAC and AKAP13-∆PKD1 TAC hearts (Fig 12B–12E).


Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.

Johnson KR, Nicodemus-Johnson J, Spindler MJ, Carnegie GK - PLoS ONE (2015)

Myofilament Gene expression stratified by WT or AKAP13-∆PKD1 mice following sham or TAC surgery.Normalized (log-transformed) gene expression is shown for myofilament proteins A) Desmin (Des), B) Myosin binding protein C-2 (MybpC2), C) Troponin T1 (Tnnt1), D) Myosin binding protein C-3, E) Popeye protein-3 (Popcd3), and F) Ankyrin repeat domain 23 (Ankrd23). Gray boxes represent the interquartile range, encompassing the first through third quartiles; the horizontal bar shows the median value. Values greater than 1.5 times the interquartile range are plotted outside of the whiskers. P values are from linear regression assuming an additive model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508115&req=5

pone.0132474.g008: Myofilament Gene expression stratified by WT or AKAP13-∆PKD1 mice following sham or TAC surgery.Normalized (log-transformed) gene expression is shown for myofilament proteins A) Desmin (Des), B) Myosin binding protein C-2 (MybpC2), C) Troponin T1 (Tnnt1), D) Myosin binding protein C-3, E) Popeye protein-3 (Popcd3), and F) Ankyrin repeat domain 23 (Ankrd23). Gray boxes represent the interquartile range, encompassing the first through third quartiles; the horizontal bar shows the median value. Values greater than 1.5 times the interquartile range are plotted outside of the whiskers. P values are from linear regression assuming an additive model.
Mentions: Select gene differential expression changes identified via microarray interrogation of WT and AKAP13-∆PKD1 hearts were sub-categorized into myofilament, apoptosis, cell growth/differentiation, energy metabolism, or oxidative stress–related molecules (Figs 8–12). Myofilament-Associated Genes: Significant differences between WT-sham/TAC and AKAP13-∆PKD1-Sham/TAC were seen in multiple myofilament genes (Fig 8). Desmin (Des), myosin binding protein C-2 (MybpC-2), troponin T-1 (Tnnt1), and myosin binding protein C-3 (MybpC3) were all significantly different between WT-Sham and WT-TAC hearts but not between AKAP13-∆PKD1-sham and TAC hearts. The cardiac muscle development-associated gene Popdc3 is elevated in both WT and AKAP13-∆PKD1 TAC hearts compared to sham, though at different significance level (Fig 8E). The stretch-induced transcription factor Ankrd23 is elevated in both WT-TAC and AKAP13-∆PKD1 TAC compared to sham hearts (Fig 8F). Apoptosis-Associated Genes: Significantly elevated apoptosis gene expression levels were identified in WT-TAC but not GT-TAC for Fadd and Bcl2 (Fig 9A and 9B). Expression levels for the genes Bax, Nudt1, and Gzmm are significantly reduced in WT-TAC but not AKAP13-∆PKD1 TAC compared to sham (Fig 9C–9E). Cell growth and differentiation-associated genes: Significantly elevated expression of Nuak1 was seen in WT-TAC but not GT-TAC (Fig 10A), while significantly reduced expression of Igf2 and Tgfβr3 was seen in WT-TAC but not AKAP13-∆PKD1 TAC (Fig 10B and 10C). Significantly elevated expression of both Tgfb3 and Emp1 are seen in WT-TAC and AKAP13-∆PKD1 TAC (Fig 10D and 10E). Metabolism-associated genes: Significant reduction in Etfb expression was found in WT-TAC but not AKAP13-∆PKD1 TAC hearts (Fig 11A). Several other energy metabolism-related genes were significantly altered in both WT-TAC and AKAP13-∆PKD1 TAC hearts, though at different significance levels (Fig 11B–11E). Oxidative stress response genes: Expression of the oxidative stress-response gene Sod1 was significantly reduced in WT-TAC hearts but not in AKAP13-∆PKD1 TAC hearts (Fig 12A). Other oxidative stress-response genes had similar expression profiles for WT-TAC and AKAP13-∆PKD1 TAC hearts (Fig 12B–12E).

Bottom Line: Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612, IL, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus