Loss of<i>Prox1</i>in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

Petchey, Louisa K.; Risebro, Catherine A.; Vieira, Joaquim Miguel; Roberts, Thomas A.; Bryson, John B.; Greensmith, Linda; Lythgoe, Mark F.; Riley, Paul R.

doi:10.1073/pnas.1406191111

Cited by 45 publications

(45 citation statements)

References 40 publications

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“…VEGFR3 expression in inflammatory cells and blood vessels as well as the role of VEGFC in lipid absorption also introduce confounding variables. [146][147][148] We recently found a surprising novel mechanism that regulates dietary lipid uptake and obesity development in the VEGFC-deleted mice. 8,149 Deletion of VEGFC in adult mice, which have a normally developed lymphatic system, does not result in adverse effects on animal health even 6 months after gene deletion.…”

Section: Obesitymentioning

confidence: 99%

Lymphatic System in Cardiovascular Medicine

Aspelund

Robciuc

Karaman³

et al. 2016

Circulation Research

266

258

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Abstract:The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

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Section: Obesitymentioning

confidence: 99%

Lymphatic System in Cardiovascular Medicine

Aspelund

Robciuc

Karaman³

et al. 2016

Circulation Research

266

258

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“…Among lymphatic transcriptional regulators, Prox1 has emerged as the master transcription factor responsible for inducing and maintaining LEC identity. Interestingly, Prox1 plays a parallel role in cardiomyocytes, where it regulates cardiac hypertrophic responses 32 , as well as the switch between expression of fast-twitch and slow-twitch muscle genes in heart 33 and skeletal muscle 34 . Indeed, cardiomyocyte-specific Prox1-deficiency in mice leads to overexpression of fast-twitch muscle genes and development of early-onset dilated cardiomyopathy (DCM) 33 .…”

Section: Lymphatic Vasculature: Structure and Function And Remodelingmentioning

confidence: 99%

“…Interestingly, Prox1 plays a parallel role in cardiomyocytes, where it regulates cardiac hypertrophic responses 32 , as well as the switch between expression of fast-twitch and slow-twitch muscle genes in heart 33 and skeletal muscle 34 . Indeed, cardiomyocyte-specific Prox1-deficiency in mice leads to overexpression of fast-twitch muscle genes and development of early-onset dilated cardiomyopathy (DCM) 33 . In adults, lymphatic vessels are quiescent, similar to blood vessels, except during tissue remodeling, for example in the intestine 35,36 .…”

Section: Lymphatic Vasculature: Structure and Function And Remodelingmentioning

confidence: 99%

Cardiac lymphatics in health and disease

2018

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The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in for maintenance of tissue fluid homeostasis, immune cell trafficking and nutritional lipid uptake and transport, as well as reverse cholesterol transport. In this review, we discuss the physiological role of lymphatics in the heart, in maintenance of cardiac health, and describe alterations of lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We further discuss briefly the role that immune cells may play in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide recent examples of how the cardiac lymphatics may be targeted therapeutically to restore lymphatic drainage in the heart in order to limit myocardial edema and chronic inflammation. Key points  Cardiac lymphatics display a dynamic range of fluid uptake and transport, linked to cardiac contractility and heart rate  Cardiac lymphatics undergo significant remodeling in several cardiovascular diseases, which can alter the lymphatic drainage capacity in the heart  Insufficient lymphangiogenesis may contribute to the buildup of atherosclerotic lesions in large arteries due to accumulation of both lipids and activated immune cells  Immune cells contribute to the process of lymphatic remodeling by stimulating or inhibiting lymphangiogenesis  Therapeutic stimulation of cardiac lymphangiogenesis after myocardial infarction leads to accelerated resolution of myocardial edema and inflammation, promoting cardiac recovery

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“…Although certain acquired risk factors have been implicated in DCM, including viral myocarditis, myocardial infarction, arrhythmias and autoimmune disorders (4), in the majority of patients with DCM no secondary etiologies can be identified, this is defined as idiopathic DCM, among which 25-50% of DCM occur in at least two close relatives, hence termed familial DCM, and familial transmission of DCM has been observed to occur in an autosomal dominant, autosomal recessive or X-linked manner with variable expressivity and penetrance (1). Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of idiopathic DCM, and mutations in >50 genes have been causally linked to idiopathic DCM (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Nevertheless, these established DCM-associated genes are observed in less than a third of all cases and the genetic determinants underpinning DCM in an overwhelming majority of patients remain unclear (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy

Fang

et al. 2015

Molecular Medicine Reports

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Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of ~0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co-segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM.

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Loss ofProx1in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

Cited by 45 publications

References 40 publications

Lymphatic System in Cardiovascular Medicine

Lymphatic System in Cardiovascular Medicine

Cardiac lymphatics in health and disease

Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy

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