Mixed Messages

Margulies, Kenneth B.; Matiwala, Sunil; Cornejo, Carla; Olsen, Henrik S.; Craven, William A.; Bednarik, Daniel P.

doi:10.1161/01.res.0000159390.03503.c3

Cited by 165 publications

(76 citation statements)

References 30 publications

(31 reference statements)

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“…All subjects provided written informed consent. Flash-frozen left ventricular myocardial samples from heart failure patients were obtained at time of cardiac surgery as previously described (39,40). Subjects with advanced systolic heart failure were recruited into one of two National Heart, Lung, and Blood Institute-funded longitu- Table 2.…”

Section: Methodsmentioning

confidence: 99%

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cappola

Matkovich

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K a renal chloride channel (ClC-K a ). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10 −6). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10 −7). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K a chloride channel currents revealed ≈50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardiorenal axis.cardiomyopathy | genetic association

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Section: Methodsmentioning

confidence: 99%

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cappola

Matkovich

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Margulies et al 68 performed a global transcription analysis of 199 human heart samples using the Affymetrix GenChip HG_U133 Array and observed 3,088 genes with expression that was significantly different between 113 failing hearts and 6 non-failing hearts. Interestingly, of these 3,088 genes, only 238 showed a consistent response to support with a LVAD.…”

Section: Changes In the Gene Expression In The Failing Myocardium Aftmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568 -1576

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“…Furthermore, LVADs have been shown to lead to partial normalization of myocardial structure and function, including increased ␤-AR responsiveness (30); decreased myocyte volume (40), width (41), and diameter (22); and improved myocyte contractility (10) in a process termed "reverse remodeling." We were the first to report both global and etiology-specific differential gene expression using paired tissue samples from patients in end-stage HF and following LVAD-mediated reverse remodeling, followed by several other reports (4,5,15,24). These tissue samples provide a powerful model to investigate progression and regression of HF with patients as their own reference, eliminating the confounding factors of human heterogeneity.…”

mentioning

confidence: 99%

Identification of Nogo as a novel indicator of heart failure

Bullard

Protack

Aguilar

et al. 2008

Physiological Genomics

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Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant β-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gβγ inhibitory carboxy-terminus of the β-adrenergic receptor kinase (βARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their βARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP−/−), which closely parallels human dilated cardiomyopathy disease progression and aberrant β-adrenergic signaling, and their βARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP−/− subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.

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Mixed Messages

Cited by 165 publications

References 30 publications

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Global Gene Expression Profiling in the Failing Myocardium

Identification of Nogo as a novel indicator of heart failure

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