Young MLP deficient mice show diastolic dysfunction before the onset of dilated cardiomyopathy

Lorenzen‐Schmidt, Ilka; Stuyvers, Bruno D.; Keurs, H. E. D. J. Ter; Date, Motoo; Hoshijima, Masahiko; Chien, Kenneth R.; McCulloch, Andrew D.; Omens, Jeffrey H.

doi:10.1016/j.yjmcc.2005.05.006

Cited by 34 publications

(33 citation statements)

References 38 publications

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“…As reported previously, 23,[35][36][37] MLPKO hearts show an increase in passive stiffness. Normalization of the LVEDP in the DKO hearts indicated that the impaired filling in the MLPKO hearts was rectified in the absence of the AT1a receptor (Table 2).…”

Section: Gene Expressions In Mlpko and Dko Heartssupporting

confidence: 85%

Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

Yamamoto

Akazawa

Ito

et al. 2007

Circ J

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growing body of evidence suggests that blockade of the renin -angiotensin system (RAS) leads to a decrease in the morbidity and mortality of patients with congestive heart failure. 1 In addition to the systemic effects, including elevation of blood pressure (BP), sodium and water retention, and activation of the sympathetic nervous system, the activated RAS has unfavorable direct effects on the heart. 2 Most of the known functions of angiotensin II (Ang II) in the cardiovascular system are mainly mediated through the Ang II type 1 (AT1) receptor. 3 In mice or rats, the AT1 receptor has 2 subtypes (AT1a and AT1b), but the AT1a receptor is predominantly expressed and functionally important in cardiomyocytes. 4,5 According to the results of in vitro experiments, activation of the AT1 receptor stimulates diverse intracellular signaling cascades and produces reactive oxygen species, which evoke hypertrophic responses in cardiomyocytes and enhance cellular proliferation and production of extracellular matrix proteins, such as collagen, in cardiac fibroblasts. 2,6 These cellular alterations that occur within the heart would promote left ventricular (LV) remodeling and contribute to the progression of heart failure. However, the effects of the AT1 receptor have been experimentally verified only in animal models of heart failure, such as a myocardial infarction model produced by coronary artery ligation, 7-9 a pacing-induced heart failure model, 10 Dahl salt-sensitive rats, 11 a pressure-overloaded model, 12,13 a shunt-induced volume-overloaded model, 14 experimental myocarditis, 15 and doxorubicininduced cardiomyopathy. 16 A number of reports have suggested that inhibition of the AT1 receptor prevents LV remodeling after myocardial infarction, 2,7-9 but it remains unknown whether it is also beneficial for dilated cardiomyopathy (DCM).Mice deficient for the gene for muscle LIM protein (MLP) have been characterized as a good model of human DCM. 17 MLP, a member of the LIM-only proteins, 18 is involved in organization of cytoarchitecture 17 and is proposed to function as a mechanosensor. 19 Approximately 35% of MLP-deficient mice (offspring of homozygous breeders) exhibit an early phenotype with marked hypertrophy and death within 10-11 days, and remainder survive into adulthood and exhibit a number of phenotypic features of human DCM (adult phenotype). 17 In the present study, we used MLP-deficient mice as a model of DCM and examined the effects of AT1 receptor blockade on disease progression using AT1a-deficient mice. Methods AnimalsG1 pups generated from an MLP +/-heterozygote× AT1a -/-homozygote cross were mated to created the MLP +/-/ AT1a +/-double heterozygotes (G2). G4 offspring were genCirc J 2007; 71: 1958 -1964 (Received March 29, 2007 revised manuscript received July 20, 2007; accepted July 31, 2007 Background Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbi...

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Section: Gene Expressions In Mlpko and Dko Heartssupporting

confidence: 85%

Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

Yamamoto

Akazawa

Ito

et al. 2007

Circ J

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“…This is consistent with studies in titin N2B-deficient mice, which demonstrate that the N2B region of titin affects diastolic but not systolic function of the heart (31). Multiple mechanisms of titin-based stretch sensing and signaling pathways have been proposed within the central I band (5,32). However, our studies demonstrate an in vivo role for the titin N2B binding partner, FHL1, in diastolic function and biomechanical stress responses involved in pressure overload-induced hypertrophy.…”

Section: Discussionmentioning

confidence: 55%

“…LVIDd, LV internal dimension at end-diastole. *P < 0.05; **P < 0.01. results of studies in MLP- and titin N2B-deficient mice, in which the reduced passive tension and basal cardiac muscle defects were likely due to shortened sarcomere slack lengths (4,31,32). Extracellular collagen is one of the major contributors to myocardial diastolic tension at longer sarcomere lengths (43).…”

Section: Discussionmentioning

confidence: 99%

An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice

Sheikh¹,

Raskin²,

Chu³

et al. 2008

J. Clin. Invest.

217

232

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The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that fourand-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress-induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the Gαq (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin-and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.

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“…Based on the phenotype of young MLP -/-mice, it has been proposed that the progression to heart failure in the MLP deficiency model may be driven by diastolic dysfunction and abnormal passive properties rather than systolic dysfunction (Lorenzen-Schmidt et al, 2005). MLP interacts with Tcap, and mutations in the Tcap binding region of MLP have been found in a subset of patients with dilated cardiomyopathy (Knöll et al, 2002).…”

Section: Candidate Partners Of Z-disc-associated Proteins In the Strementioning

confidence: 99%

TheDrosophilamuscle LIM protein, Mlp84B, is essential for cardiac function

Méry

Taghli-Lamallem

Clark

et al. 2008

Journal of Experimental Biology

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SUMMARYMuscle LIM protein (MLP) is a cytoskeletal protein located at the Z-disc of sarcomeres. Mutations in the human MLP gene are associated with hypertrophic and dilated cardiomyopathy. MLP has been proposed to be a key player in the stretch-sensing response, but the molecular mechanisms underlying its function in normal and diseased cardiac muscle have not been established. A Drosophila homolog, Mlp84B, displays a similar subcellular localization at the Z-disc of sarcomeres throughout development and in the adult, suggesting Drosophila as a model to study MLP function. Here we employed genetic ablation and cardiac-specific RNA interference (RNAi) knockdown of mlp84B to investigate its role in heart function. We found that Mlp84B-deficient or heart-specific RNAi knockdown flies exhibit diastolic interval prolongation, heart rhythm abnormalities and a reduced lifespan, while showing no obvious structural phenotype. Our data demonstrate that Mlp84B is essential for normal cardiac function and establish the Drosophila model for the investigation of the mechanisms connecting defective cardiac Z-disc components to the development of cardiomyopathy. Supplementary material available online at

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Young MLP deficient mice show diastolic dysfunction before the onset of dilated cardiomyopathy

Cited by 34 publications

References 38 publications

Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice

TheDrosophilamuscle LIM protein, Mlp84B, is essential for cardiac function

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