Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy

Kimura, Hirotaka; Eguchi, Satoshi; Sasaki, Junko; Kuba, Keiji; Nakanishi, Hiroki; Takasuga, Shunsuke; Yamazaki, Masakazu; Goto, Akiteru; Watanabe, Hiroyuki; Itoh, Hiroshi; Imai, Yumiko; Suzuki, Akira; Mizushima, Noboru; Sasaki, Takehiko

doi:10.1172/jci.insight.89462

Cited by 19 publications

(14 citation statements)

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“…To confirm that assertion, we examined the effects of gene knockout of PIK3C3, which encodes a protein involved in the nucleation of pre-autophagosomal structures 52 , and ULK1, which encodes a direct activator of PIK3C3 complex 53,54 , on the antiviral activity of PVF-tet. The MDCK-derived knockout clones of these genes were confirmed to have suppressed protein expression ( Fig.…”

Section: Resultsmentioning

confidence: 96%

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection

et al. 2020

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The emergence of drug-resistant influenza type A viruses (IAVs) necessitates the development of novel anti-IAV agents. Here, we target the IAV hemagglutinin (HA) protein using multivalent peptide library screens and identify PVF-tet, a peptide-based HA inhibitor. PVF-tet inhibits IAV cytopathicity and propagation in cells by binding to newly synthesized HA, rather than to the HA of the parental virus, thus inducing the accumulation of HA within a unique structure, the inducible amphisome, whose production from the autophagosome is accelerated by PVF-tet. The amphisome is also produced in response to IAV infection in the absence of PVF-tet by cells overexpressing ABC transporter subfamily A3, which plays an essential role in the maturation of multivesicular endosomes into the lamellar body, a lipidsorting organelle. Our results show that the inducible amphisomes can function as a type of organelle-based anti-viral machinery by sequestering HA. PVF-tet efficiently rescues mice from the lethality of IAV infection.

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Section: Resultsmentioning

confidence: 96%

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection

et al. 2020

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“…A corresponding impact on the expression of VPS34 interactors such as VPS15 in these models makes protein‐specific phenotype interpretation more challenging, but the comparable embryonic lethality of knock‐out and kinase‐dead knock‐in mice supports a role for this enzyme in early embryonic development, with defects in cell proliferation and mTOR signalling [133,138]. Tissue‐specific targeting has allowed further insight into the physiological roles of VPS34, with loss of VPS34 leading to cardiomyopathy and cardiomegaly in the heart [139,140], hepatomegaly and hepatic steatosis in the liver [139], rod cell degeneration in the retina [141], neurodegeneration in the nervous system [142–144], and defective T cell survival and homeostasis [145,146]. Many of these phenotypes were associated with defects in cellular autophagy or endocytic trafficking.…”

Section: Class III Pi3kmentioning

confidence: 99%

PI3K inhibitors in thrombosis and cardiovascular disease

Durrant

Hers²

2020

Clinical & Translational Med

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Phosphoinositide 3‐kinases (PI3Ks) are lipid kinases that regulate important intracellular signalling and vesicle trafficking events via the generation of 3‐phosphoinositides. Comprising eight core isoforms across three classes, the PI3K family displays broad expression and function throughout mammalian tissues, and the (patho)physiological roles of these enzymes in the cardiovascular system present the PI3Ks as potential therapeutic targets in settings such as thrombosis, atherosclerosis and heart failure. This review will discuss the PI3K enzymes and their roles in cardiovascular physiology and disease, with a particular focus on platelet function and thrombosis. The current progress and future potential of targeting the PI3K enzymes for therapeutic benefit in cardiovascular disease will be considered, while the challenges of developing drugs against these master cellular regulators will be discussed.

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“…Myofibers of CMs show disarray at the ultrastructural level: intermittence, shortening of Zlines, expansion of interfibrillar spaces and increase in the number of intra and intermyofibrillar couplings. H. Kimura et al report that hypertrophy and destruction of myosin filaments is characteristic ultrastructural feature of HCM [54] and may play a key role in heart failure progression [55]. The pathology of intercellular junctions in myocardial disarray is of special attention.…”

Section: обзорыmentioning

confidence: 99%

Myocardial morphology in hypertrophic cardiomyopathy: the current state of the problem

Balabai

2019

ZMJ

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Цель работы -на основании данных современных источников научной литературы проанализировать морфологические особенности миокарда при гипертрофической кардиомиопатии.Обзор освещает современные взгляды на особенности структурного ремоделирования миокарда левого желудочка сердца у больных гипертрофической кардиомиопатией, приведены наиболее распространенные классификации данной патологии. Уделено внимание проблеме взаимосвязи фигур дизарея кардиомиоцитов и фиброза миокарда. Важное патогенетическое звено развития сердечной недостаточности, усиливающее связь между нарушениями гистоархитектоники миокарда и прогрессирующей ишемией сердца при гипертрофической кардиомиопатии -«болезнь малых сосудов».Выводы. Несмотря на большое количество исследований гипертрофической кардиомиопатии, в научной литературе нет единого мнения об этиологии и патогенезе гипертрофической кардиомиопатии. Противоречивые сведения о наличии взаимосвязи и последовательности развития фигур дизарея, гипертрофии кардиомиоцитов, интерстициального фиброза, изменений микроциркуляторного русла и митрального клапана при гипертрофической кардиомиопатии затрудняют поиски адекватного этиотропного лечения. Полиморфизм клинических и морфологических проявлений гипертрофической кардио миопатии требует от кардиологов и патогистологов совместных усилий по изучению данной болезни.A -research concept and design; B -collection and/or assembly of data; C -data analysis and interpretation; D -writing the article; E -critical revision of the article; F -final approval of the article The objective. Based on the modern sources of scientific data to analyze the morphological features of the myocardium in hypertrophic cardiomyopathy.The paper presents a literature review on current views on the features of structural remodeling of the left ventricular myocardium in patients with hypertrophic cardiomyopathy, as well as the most common classifications of this pathology. The emphasis is made on the problem of the interrelation of myocardial disarray and fibrosis.The "small vessel disease" is an important pathogenetic link in the development of heart failure, which enhances the relation between disorder of myocardial histoarchitectonics and progressive cardiac ischemia in hypertrophic cardiomyopathy. Conclusions.Notwithstanding the numerous research data on hypertrophic cardiomyopathy, no consensus among the authors regarding the etiology and pathogenesis of hypertrophic cardiomyopathy exists to date. Controversial data on the interrelation and sequence of disarray, myocardial hypertrophy, interstitial fibrosis, changes in the microvasculature and structural changes of the mitral valve in patients with hypertrophic cardiomyopathy hamper the search for adequate etiotropic treatment.Polymorphism of clinical and morphological manifestations of hypertrophic cardiomyopathy requires collaborative efforts to study the disease by cardiologists and pathologists.Морфологія міокарда при гіпертрофічній кардіоміопатії: сучасний стан проблеми А. А. Балабай Мета роботи -на підставі даних сучасни...

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Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy

Cited by 19 publications

References 50 publications

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection

PI3K inhibitors in thrombosis and cardiovascular disease

Myocardial morphology in hypertrophic cardiomyopathy: the current state of the problem

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