Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the β-adrenergic and renin-angiotensin systems

Champetier, Serge; Bojmehrani, Azadeh; Beaudoin, Jonathan; Lachance, Dominic; Plante, Eric; Roussel, Élise; Couët, Jacques; Arsenault, Marie

doi:10.1152/ajpheart.01046.2008

Cited by 33 publications

(34 citation statements)

References 40 publications

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“…[ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG) (30–40 MBq, in 0.3 ml plus 0.1 ml flush of 0.9% NaCl) was injected via the caudal vein over 30 s. A 45-min dynamic PET data acquisition followed by a 15-min static acquisition was done to determine glucose utilization [myocardial metabolic rate of glucose (MMRG)] using multicompartmental analysis as previously described [32, 33]. The static scan served to draw regions-of-interest (ROIs) on each segment of the LV wall.…”

Section: Methodsmentioning

confidence: 99%

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

Lachance

Dhahri

Drolet

et al. 2014

BMC Cardiovasc Disord

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BackgroundPatients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR.MethodsLV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months.ResultsMicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them.ConclusionThis study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-190) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

Lachance

Dhahri

Drolet

et al. 2014

BMC Cardiovasc Disord

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“…The analysis of LV mRNA levels by quantitative RT-PCR has been described in details elsewhere [17]. Briefly, one µl RNA (500 ng) was converted to cDNA using the QuantiTect Reverse Transcription kit (Qiagen, Valencia, CA).…”

Section: Analysis Of Mrna Accumulation By Quantitative Rt-pcrmentioning

confidence: 99%

Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

Dhahri¹

2012

J Clin Exp Cardiolog

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Aims: Left ventricular hypertrophy (LVH) is often associated with a change in myocardial energy substrate preference from fatty acids to glucose. A possible antihypertrophic treatment strategy could aim at stimulating or restoring normal myocardial energy metabolism. Metformin, an adenosine monophosphate-activated protein kinase (AMPK) activator used in the management of glucose metabolism in diabetes, is also a fatty acid oxidation stimulator. The effect of metformin on the development of eccentric LVH and ventricular function in chronic left ventricular (LV) volume overload (VO) is unknown. This study was designed to study this question in a VO rat model caused by severe aortic valve regurgitation (AR). Methods:Male Wistar rats were divided in four groups (13-15 animals / group): Shams (S) treated or not (C) with metformin (M; 100 mg/kg/d PO) and severe AR receiving or not metformin. Treatment was started one week before surgery and the animals were sacrificed 9 weeks later. Results:As expected AR rats developed severe eccentric LVH during the course of the protocol. Metformin treatment did not influence the total heart weight. However, LV remodeling associated with the severe VO was severe in ARM than in ARC. Fractional shortening, a marker of systolic function, was significantly higher in ARM compared to ARC group. Metformin also increased the activity of enzymes associated with fatty acid oxidation while inhibiting phosphofructokinase, a glycolytic enzyme. Conclusion:A 2 month treatment with metformin reduced LV eccentric remodeling associated with severe VO and helped maintain a better systolic function.

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“…In rats with traumatic acute AR, increased expression of some fetal genes and collagen isoforms occurs early, and persists essentially unchanged for months. 22 Our findings in Wave mice with spontaneous chronic AR differ somewhat in that increased expression of fetal genes is progressive over 12 months, and myocardial expression of collagen-1,3 is normal during the early period of LV compensation in the presence of volume overload. Our findings thus dissociate upregulation of myocardial collagen isoform expression from volume overload per se , a novel finding.…”

Section: Discussionmentioning

confidence: 54%

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Hajj

Chu

Lund

et al. 2015

ATVB

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Objective We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice. Approach and Results At 1.5 months of age, prior to development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, pro-fibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age. Conclusions We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction, and are epiphenomena arising from structurally incompetent “myxomatous” valves.

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Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the β-adrenergic and renin-angiotensin systems

Cited by 33 publications

References 40 publications

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

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