Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy

Depré, Christophe; Shipley, Gregory L.; Chen, Wenhao; Han, Qiuying; Doenst, Torsten; Moore, Meredith; Stepkowski, Stanislaw M.; Davies, Peter J.; Taegtmeyer, Heinrich

doi:10.1038/3253

Cited by 391 publications

(321 citation statements)

References 53 publications

(54 reference statements)

Supporting

Mentioning

295

Contrasting

Unclassified

Order By: Relevance

“…Several studies have shown that DNA microarrays can be used in cardiovascular aging research to generate panels of hundreds of transcriptional biomarkers Bodyak et al ., 2002). The gene expression profile of aging cardiomyocyte shows similarities to profiles of known heart disorders, such as ischemic heart disease and cardiomyopathies (Depre et al ., 1998;Juhasz et al ., 2002).…”

Section: Introductionmentioning

confidence: 97%

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Maejima¹,

Adachi²,

Ito³

et al. 2007

Aging Cell

168

130

View full text Add to dashboard Cite

SummaryCellular senescence is an important phenomenon in decreased cellular function. Recently, it was shown that cellular senescence is induced in proliferating cells within a short period of time by oxidative stresses. This phenomenon is known as premature senescence. However, it is still unknown whether premature senescence can be also induced in cardiomyocytes. The aim of the present study was to investigate whether a senescence-like phenotype can be induced in cardiomyocytes by oxidative stress. In cardiomyocytes obtained from aged rats (24 months of age), the staining for senescence-associated β β β β -galactosidase increased significantly and the protein or RNA levels of cyclin-dependent kinase inhibitors increased compared to those of young rats. Decreased cardiac troponin I phosphorylation and telomerase activity were also observed in aged cardiomyocytes. Treatment of cultured neonatal rat cardiomyocytes with a low concentration of doxorubicin (DOX) (10 -7 mol L -1 ) did not induce apoptosis but did induce oxidative stress, which was confirmed by 2′ ′ ′ ′ ,7′ ′ ′ ′ -dichlorofluorescin diacetate staining. In DOX-treated neonatal cardiomyocytes, increased positive staining for senescence-associated β β β β -galactosidase, cdk-I expression, decreased cardiac troponin I phosphorylation, and decreased telomerase activity were observed, as aged cardiomyocytes. Alterations in mRNA expression typically seen in aged cells were observed in DOX-treated neonatal cardiomyocytes. We also found that promyelocytic leukemia protein and acetylated p53, key proteins involved in stressinduced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes. In conclusion, cardiomyocytes treated with DOX showed characteristic changes similar to cardiomyocytes of aged rats. promyelocytic leukemiarelated p53 acetylation may be an underlying mechanism of senescence-like alterations in cardiomyocytes. These findings indicate a novel mechanism of myocardial dysfunction induced by oxidative stress.

show abstract

Section: Introductionmentioning

confidence: 97%

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Maejima¹,

Adachi²,

Ito³

et al. 2007

Aging Cell

168

130

View full text Add to dashboard Cite

show abstract

“…2 The molecular pathways that underpin this process remain complex but include re-expression of a 'fetal gene program,' the induction of growth factors such as transforming growth factor-b, the re-expression of proto-oncogenes (such as c-fos) and the activation of neurohormones, including angiotensin-II, endothelin-1 and norepinephrine. 3 The resultant pathological changes seen include myocyte hypertrophy, local fibroblast proliferation and alterations in the myocardial extracellular matrix. 4,5 It is widely accepted that blood pressure control is central in the prevention of the adverse effects of hypertension on the cardiovascular system.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

View full text Add to dashboard Cite

Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

show abstract

“…28 Improving cardiac metabolism has been postulated as a novel treatment of heart failure. 23,29 It has been shown that in animal models of obesity 35 and in humans with no other co-morbidity, abnormally low PCr/ATP ratios occur at rest, potentially due to, in addition to changes in substrate utilization, a loss of the total creatine pool in proportion to the loss of PCr, as occurs in many other forms of hypertrophy. 1,[78][79][80][81] Furthermore, this has been linked to altered cardiac diastolic function and is exacerbated during catecholamine stress.…”

Section: Cardiac Energetics and Obesitymentioning

confidence: 99%

“…21 The importance is again highlighted in the setting of heart failure and left ventricular (LV) hypertrophy, where mitochondrial oxidative capacity is reduced and metabolism shifts back towards a reliance on glucose metabolism, resembling the fetal metabolic program. 22,23 As the heart is an extremely efficient scavenger of circulating non-esterified FFAs (up to 40% extraction fraction), 24 the rate of fatty-acid uptake by the heart is primarily determined by the concentration of non-esterified fatty acids in the plasma. 25 The concentration of serum FFAs is highly regulated and represents a balance between production via hormone-sensitive lipaseinduced adipose tissue triglyceride breakdown and synthesis via glycerolphosphate acyltransferase.…”

Section: Introductionmentioning

confidence: 99%

Myocardial substrate metabolism in obesity

et al. 2012

View full text Add to dashboard Cite

Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure. (2013) Keywords: myocardial metabolism; review; obese INTRODUCTION Cardiac energy metabolism is essentially a four-step process involving the following: (1) myocellular substrate uptake/selection, (2) mitochondrial ATP production and (3) ATP transfer from the site of production (mitochondrion) to (4) the site of ATP utilization (cardiac myofibril; Figure 1). 1 Although glycolysis is an ATP generator, the overall ATP production is controlled largely by the rate at which the Krebs (tricarboxylic acid) cycle operates. 2 Acetyl co-enzyme A (CoA), which is produced from the oxidation of fatty acids, ketone bodies, or glucose via glycolysis, and the pyruvate dehydrogenase (PDH) enzyme complex 3 enters the Krebs cycle for complete oxidation. During oxidative phosphorylation, electrons, primarily obtained from oxidative metabolism of carbohydrates and fats, are transferred through the electron transport chain, a fourcomplex protein system embedded within the inner membrane of the mitochondria. The major function of the electron transport chain is to produce a proton electrochemical potential difference between two compartments that powers ATP synthase to generate ATP, which is used for all cardiac cellular processes. 4 ATP is the heart's only immediate source of energy for contraction, and as both systole and diastole are ATP-consuming processes, 5,6 cardiac ATP demand is very high. To keep up with this demand for continuous and efficient contraction and relaxation, the heart needs to produce around 20 times its own weight in ATP per day. 1 As a result of this large energy requirement, any impairment in ATP production, transfer or utilization can have detrimental effects on cardiac function. 7 Cardiac metabolism and ATP production is altered in obesity and has emerged as a candidate mechanism to explain the increase in heart failure in this population. 8 Indeed, it has recently been shown that obesity, in the absence of co-morbiditie...

show abstract

Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy

Cited by 391 publications

References 53 publications

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Myocardial substrate metabolism in obesity

Contact Info

Product

Resources

About