Dataset Information

Vinculin-network mediated cytoskeletal remodeling regulates contractile function in the aging heart - Rat Data

ABSTRACT: The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. Here we present the proteomes of rhesus monkeys and rats, from which we show that age-associated remodeling of the cardiomyocyte cytoskeleton is highly-conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirms conservation and implicates vinculin as a unique regulator of cardiac aging. Increased cardiac vinculin expression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility, hemodynamic stress tolerance, and lifespan. These findings suggest that the heart has molecular mechanisms to sustain function and longevity which may be assisted by therapeutic intervention.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Vidya Venkatraman

LAB HEAD: Dr. Jennifer Van Eyk

PROVIDER: PXD001839 | Pride | 2016-04-15

REPOSITORIES: Pride

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Publications

Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart.

Kaushik Gaurav G Spenlehauer Alice A Sessions Ayla O AO Trujillo Adriana S AS Fuhrmann Alexander A Fu Zongming Z Venkatraman Vidya V Pohl Danielle D Tuler Jeremy J Wang Mingyi M Lakatta Edward G EG Ocorr Karen K Bodmer Rolf R Bernstein Sanford I SI Van Eyk Jennifer E JE Cammarato Anthony A Engler Adam J AJ

Science translational medicine 20150601 292

The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than del ...[more]

PMID: 26084806

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Project description:Right ventricular free wall (RVFW) pacing results in left ventricular dyssynchrony with early septal shortening followed by late lateral contraction that reciprocally stretches the septum. Dyssynchrony is disadvantageous to cardiac mechano-energetics, yet little is known about its molecular consequences. We tested the hypothesis that dyssynchrony selectively alters regional gene expression in mice, employing a novel miniature implantable cardiac pacemaker. Mice were subjected to 1-week overdrive RVFW pacing (720 min-1, baseline HR 520-620 min-1) to induce dyssynchrony (pacemaker: 3V lithium battery, rate programmable, 0.8 grams, bipolar lead). Electrical capture was confirmed by pulsed-wave Doppler at implantation and terminal study, and dyssynchrony by echocardiography. Gene expression from left ventricular septal and lateral-wall myocardium were assessed by microarray (dual-dye method, Agilent) using oligonucleotide probes and dye swap. Identical analysis was applied to 4 synchronously contracting controls. Of 22,000 genes surveyed, only 18 genes displayed significant (p<0.01) differential expression between septal/lateral walls exceeding 1.5-fold relative to any disparities in synchronous controls. These changes were confirmed by qPCR with excellent correlations. Most (16) of the genes showed greater septal expression. Of particular interest were 7 genes coding proteins involved with stretch responses, matrix remodeling, stem cell differentiation to myocyte lineage, and Purkinje fiber differentiation. One-week cardiac dyssynchrony triggers regional differential expression differences in relatively few select genes. Such analysis using a murine implantable pacemaker should facilitate molecular studies of cardiac dyssynchrony and help elucidate novel mechanisms by which stress/stretch stimuli due to dyssynchrony impact the normal and failing heart. Experiment Overall Design: Left ventricle segments from the mouse heart - septal and lateral, were isolated from 4 dyssynchronous mice that were kept separate. RNA from the synchronous mice were pooled into a control septal and lateral sample. Functional genomic analysis was conducted on these 10 RNA samples with fluorophore reversal, such that each sample was assayed on two different microarrays. Corresponding septal and lateral samples from the same heart were paired on the same microarray to measure the relative differences in gene expression between the different regions of the heart then differences were compared across multiple mice to find overlapping genes that were affected by the pacememaker implantation.

Project description:After induction of ischemic chronic heart failure (CHF), mice exhibited depression-like behavior, in terms of increased anhedonia, and decreased both exploratory activity and interest in novelty. On histology, ischemic CHF mice showed no alterations in overall cerebral morphology. To further evaluate relevant behavioral changes found in CHF mice, RNA-sequencing analysis of prefrontal cortex and hippocampus - the brain regions, whose structural and functional alterations are associated with an increased risk for developing major depressive disorder - and of left myocardial tissue was performed in CHF vs. sham-operated animals. RNA-sequencing revealed relevant changes in hippocampal or prefrontal cortical expression of genes responsible for axonal vesicle transport (Kif5b), signal transduction (Arc, Gabrb2), limitation of inflammation (RORA; Nr4a1) and of hypoxic brain damage (Hif3a). Besides, the actual literature describes some of the genes (RORA, Gabrb2, Npas4, and Junb) being associated with depression-like behavior. Nr4a1 significantly regulated in both brain and heart tissue after induction of ischemic CHF could be a potential link and reveals the central role of inflammation in the interrelation of the brain and the failing heart. Heart failure vs. sham-operation were performed in C57BL/6 male mice. After development of chronic heart failure (CHF) 8 weeks after the operation RNA was extracted out of prefrontal cortex, hippocampus and left ventricular myocardium in both groups. RNA of 3 ischemic CHF mice versus 6 sham operated mice was pooled and further subjected to RNA sequencing. To fabricate singular pools each probe of the group equally contributed with the final amount of 2 µg RNA per pool with the result that we had 6 different pools to be further evaluated. The mRNA profile was generated by IGA Technology, Italy (http://www.igatechnology.com/) by deep sequencing, using Illumina HiSeq 2000 platform (HiSeq). CLC-Bio Genomics Workbench software (CLC Bio, Denmark) was used to calculate gene expression levels based on Mortazavi et al. (Nat Methods. 2008;5:621-628) approach.

Dataset Information

Vinculin-network mediated cytoskeletal remodeling regulates contractile function in the aging heart - Rat Data

Publications

Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart.

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