Protein Kinase D3 Is a Pivotal Activator of Pathological Cardiac Hypertrophy by Selectively Increasing the Expression of Hypertrophic Transcription Factors

Li, Changlin; Li, Jing; Cai, Xuepeng; Sun, Hao; Jiao, Jinjin; Bai, Ting; Zhou, Xing; Chen, Xiongwen; Gill, Donald L.; Tang, Xiang D.

doi:10.1074/jbc.m111.263046

Cited by 22 publications

(33 citation statements)

References 40 publications

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“…One potential explanation for the down regulation of NFATC4 is competition with other biological pathways. HOXA9 indirectly promotes NFATC4 expression [51,52]. The expression of the members of the HOXA family is decreased in AAA [53].…”

Section: Resultsmentioning

confidence: 99%

MicroRNA expression signature in human abdominal aortic aneurysms

et al. 2012

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BackgroundAbdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA.MethodsTo determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®.ResultsA microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells.ConclusionsOur genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis.

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Section: Resultsmentioning

confidence: 99%

MicroRNA expression signature in human abdominal aortic aneurysms

et al. 2012

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“…Increased β-MyHC expression is a hallmark of pathological disease progression in the heart [5,33,49], and the pathological consequences of this isoform shift are beginning to emerge. Because HCM female hearts do not express elevated β-MyHC levels at earlier timepoints [5,16], these data, along with the increased SERCA2a expression and decreased PLB/SERCA2a in HCM female hearts compared to males [39], are consistent with a delayed onset of HCM disease progression in females.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic myofilament function and cardiac troponin I phosphospecies distribution in hypertrophic cardiomyopathy mice

McKee

Chen

Regan

et al. 2013

Archives of Biochemistry and Biophysics

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The pathological progression of hypertrophic cardiomyopathy (HCM) is sex dimorphic such that male HCM mice develop phenotypic indicators of cardiac disease well before female HCM mice. Here, we hypothesized that alterations in myofilament function underlies, in part, this sex dimorphism in HCM disease development. Firstly, 10–12 month female HCM (harboring a mutant [R403Q] myosin heavy chain) mice presented with proportionately larger hearts than male HCM mice. Next, we determined Ca2+-sensitive tension development in demembranated cardiac trabeculae excised from 10–12 month female and male HCM mice. Whereas HCM did not impact Ca2+-sensitive tension development in male trabeculae, female HCM trabeculae were more sensitive to Ca2+ than wild-type (WT) counterparts and both WT and HCM males. We hypothesized that the underlying cause of this sex difference in Ca2+-sensitive tension development was due to changes in Ca2+ handling and sarcomeric proteins, including expression of SR Ca2+ ATPase (2a) (SERCA2a), β-myosin heavy chain (β-MyHC) and post-translational modifications of myofilament proteins. Female HCM hearts showed an elevation of SERCA2a and β-MyHC protein whereas male HCM hearts showed a similar elevation of β-MyHC protein but a reduced level of cardiac troponin T (cTnT) phosphorylation. We also measured the distribution of cardiac troponin I (cTnI) phosphospecies using phosphate-affinity SDS–PAGE. The distribution of cTnI phosphospecies depended on sex and HCM. In conclusion, female and male HCM mice display sex dimorphic myofilament function that is accompanied by a sex- and HCM-dependent distribution of sarcomeric proteins and cTnI phosphospecies.

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“…All animals were anesthetized with diethyl ether before each experiment and efforts were made to minimize their suffering. Isolation and culture of neonatal rat ventricular myocytes (NRVM) were conducted using the overnight trypsin-collagenase digestion method as described in our recent publications [6], [19]. The experiments with NRVMs were performed on 2–4 d cultures when synchronously contracting cells were observed.…”

Section: Methodsmentioning

confidence: 99%

“…PCH develops as a result of persistent hypertension, acute myocardial infarction, genetic cardiomyopathy, and diabetes. It is characterized by cell volume increase, metabolic and biochemical abnormality, and reactivation of fetal cardiac genes such as atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC) [5], [6]. Thus, because PCH, in essence, is a maladaptive response from the very beginning, it is doomed to heart failure as unmatched cardiac cell death and fibrosis come into play.…”

Section: Introductionmentioning

confidence: 99%

CpG-ODN Attenuates Pathological Cardiac Hypertrophy and Heart Failure by Activation of PI3Kα-Akt Signaling

et al. 2013

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Phosphoinositide-3-kinase α (PI3Kα) represents a potential novel drug target for pathological cardiac hypertrophy (PCH) and heart failure. Oligodeoxynucleotides containing CpG motifs (CpG-ODN) are classic agonists of Toll-like receptor 9 (TLR9), which typically activates PI3K-Akt signaling in immune cells; however, the role of the nucleotide TLR9 agonists in cardiac myocytes is largely unknown. Here we report that CpG-ODN C274 could both attenuate PCH and improve cardiac dysfunction by activating PI3Kα-Akt signaling cascade. In vitro studies indicated that C274 could blunt reactivation of fetal cardiac genes and cell enlargement induced by a hypertrophic agent, isoproterenol. The anti-hypertrophic effect of C274 was suppressed by a pan-PI3K inhibitor, LY294002, or a small interfering RNA targeting PI3Kα. In vivo studies demonstrated that PCH, as marked by increased heart weight (HW) and cardiac ANF mRNA, was normalized by pre-administration with C274. In addition, Doppler echocardiography detected cardiac ventricular dilation, and contractile dysfunction in isoproterenol-treated animals, consistent with massive replacement fibrosis, reflecting cardiac cell death. As expected, pre-treatment of mice with C274 could prevent cardiac dysfunction associated with diminished cardiac cell death and fibrosis. In conclusion, CpG-ODNs are novel cardioprotective agents possessing antihypertrophic and anti-cell death activity afforded by engagement of the PI3Kα-Akt signaling. CpG-ODNs may have clinical use curbing the progression of PCH and preventing heart failure.

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Protein Kinase D3 Is a Pivotal Activator of Pathological Cardiac Hypertrophy by Selectively Increasing the Expression of Hypertrophic Transcription Factors

Cited by 22 publications

References 40 publications

MicroRNA expression signature in human abdominal aortic aneurysms

MicroRNA expression signature in human abdominal aortic aneurysms

Sexually dimorphic myofilament function and cardiac troponin I phosphospecies distribution in hypertrophic cardiomyopathy mice

CpG-ODN Attenuates Pathological Cardiac Hypertrophy and Heart Failure by Activation of PI3Kα-Akt Signaling

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