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Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse.

ABSTRACT: It has been recently recognized that mammalian mitochondria contain most, if not all, of the components of fatty acid synthesis type II (FAS II). Among the components identified is 2-enoyl thioester reductase/mitochondrial enoyl-CoA reductase (Etr1/Mecr), which catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters, generating saturated acyl-groups. Although the FAS type II pathway is highly conserved, its physiological role in fatty acid synthesis, which apparently occurs simultaneously with breakdown of fatty acids in the same subcellular compartment in mammals, has remained an enigma. To study the in vivo function of the mitochondrial FAS in mammals, with special reference to Mecr, we generated mice overexpressing Mecr under control of the mouse metallothionein-1 promoter. These Mecr transgenic mice developed cardiac abnormalities as demonstrated by echocardiography in vivo, heart perfusion ex vivo, and electron microscopy in situ. Moreover, the Mecr transgenic mice showed decreased performance in endurance exercise testing. Our results showed a ventricular dilatation behind impaired heart function upon Mecr overexpression, concurrent with appearance of dysmorphic mitochondria. Furthermore, the data suggested that inappropriate expression of genes of FAS II can result in the development of hereditary cardiomyopathy.

SUBMITTER: Chen Z

PROVIDER: S-EPMC2680037 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse.

Chen Zhijun Z Leskinen Hanna H Liimatta Erkki E Sormunen Raija T RT Miinalainen Ilkka J IJ Hassinen Ilmo E IE Hiltunen J Kalervo JK

PloS one 20090518 5

It has been recently recognized that mammalian mitochondria contain most, if not all, of the components of fatty acid synthesis type II (FAS II). Among the components identified is 2-enoyl thioester reductase/mitochondrial enoyl-CoA reductase (Etr1/Mecr), which catalyzes the NADPH-dependent reduction of trans-2-enoyl thioesters, generating saturated acyl-groups. Although the FAS type II pathway is highly conserved, its physiological role in fatty acid synthesis, which apparently occurs simultane ...[more]

PMID: 19440339

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Project description:AIMS:Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of ?-adrenergic/cAMP signalling. Our objective was to evaluate cardiac cAMP signalling as age increases between 2?months and 12?months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age. METHODS AND RESULTS:Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2- and 12 months old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased phosphodiesterase and PKA activity, and increased phosphorylation of several PKA targets including sarco(endo)plasmic-reticulum-calcium-ATPase (SERCA2a) cofactor phospholamban (PLN) and GSK3?/? a main regulator of hypertrophic growth and ageing. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2-month-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-month-old NTG and AC8TG, PLN and GSK3?/? phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Haemodynamics demonstrated an increased contractile function in 2- and 12-month-old AC8TG, but not in NTG. In contrast, echocardiography and tissue Doppler imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-month-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to heart failure (HF) and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG when compared with NTG. CONCLUSION:Our data demonstrated an early and accelerated cardiac remodelling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signalling can accelerate cardiac ageing, partly through GSK3?/? phosphorylation.

Project description:BackgroundEnvironmental factors are well-known causes of diseases. However, aside from a handful of risk indicators, genes' encoding susceptibility to chronic illnesses and their associated environmental triggers are largely unknown. In this era of increasingly rich diets, such genetic predispositions would be immensely helpful from a public health perspective. The novel transgenic mouse model with liver-specific NG37 overexpression characterized in this article identifies the diet-dependent function of NG37 in the pathogenesis of fatty liver disease and cardiac arrhythmia.ResultsThe liver-specific NG37 overexpression transgenic mouse model described here was generated using the Alb-SV40 polyA expression plasmid backbone. NG37 cDNA under control of the albumin promoter for liver-specific expression was fused with a 5' terminal M2 FLAG sequence and a SV40 early region transcription terminator/polyadenylation site attached at the 3'-UTR. These NG37 transgenic mice developed normally and were physiologically normal on a standard diet. However, in comparison to non-transgenic (nTG) litter mates, these mice develop dramatic phenotypes within 12-18 days of starting a high-fat diet: (i) increased body weight (28.5?±?12.3 g), (ii) increased liver weight (87.4?±?35.7 mg), (iii) increased heart weight (140?±?38.4 mg), and (iv) cardiac arrhythmia. The enlarged livers of high-fat diet NG37 transgenic mice was histologically similar to human fatty liver disease and contained Maltese cross birefringent active depositions in hepatocytes that are indicative of fatty liver disease. We also confirmed via X-ray diffraction the steatotic vesicles in the diseased hepatocytes of our high-fat diet NG37 mice was composed of cholesteryl derivatives also found in human fatty liver disease. In addition to cardiac enlargement, NG37 transgenic mice on high-fat diet also exhibited highly irregular bradycardia not present in either high-fat diet nTG littermates or normal-diet transgenic litter mates.ConclusionsThe dramatic high-fat diet-dependent symptoms (increased body weight, cardiac enlargement, fatty liver, and cardiac arrhythmias) characterized in our liver-specific NG37 overexpression mouse model identifies NG37 as a gene encoding latent lipid metabolism pathology induced only in the presence of an environmental factor relevant to human health: high-fat diet.

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Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse.

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Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse.

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