Myocardial lipofuscin accumulation in ageing and sudden cardiac death

Kakimoto, Yu; Okada, Chisa; Kawabe, Noboru; Sasaki, Ayumi; Tsukamoto, Hideo; Nagao, Ryoko; Osawa, Motoki

doi:10.1038/s41598-019-40250-0

Cited by 67 publications

(52 citation statements)

References 41 publications

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“…No changes in the levels of CTSD substrates observed in the present study indicate that the lysosomal proteolytic activity is generally maintained in the aged human heart. This is in agreement with previous reports, wherein it has been shown that autophagosome clearance is preserved in human cardiac aging [37,38]. Thus, the age-dependent upregulation of cardiac CTSD might be able to cater to the proteolytic demand during aging.…”

Section: Plos Onesupporting

confidence: 93%

Myocardial cathepsin D is downregulated in sudden cardiac death

et al. 2020

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Cathepsins are the major lysosomal proteases that maintain intracellular homeostasis. Herein, we investigated the alterations in myocardial cathepsin expression during aging, cardiac hypertrophy, and sudden cardiac death (SCD). Cardiac tissue and blood were sampled from autopsy cases. Subjects were classified into three groups: SCD with cardiac hypertrophy (SCH), compensated cardiac hypertrophy (CCH), and control. Immunoblotting was performed for the major cardiac cathepsins and their targets: cathepsin B, D, and L (CTSB/D/L), p62, ATP synthase subunit c (ATPSC), and α-synuclein (ASNC). Immunohistochemical analysis and ELISA using serum samples were performed for CTSD. Cardiac CTSB and CTSD were upregulated with age (r = 0.63 and 0.60, respectively), whereas the levels of CTSL, p62, ATPSC, and ASNC remained unchanged. In age-matched groups, cardiac CTSD was significantly downregulated in SCH (p = 0.006) and CTSL was moderately downregulated in CCH (p = 0.021); however, p62, ATPSC, and ASNC were not upregulated in cardiac hypertrophy. Immunohistochemistry also revealed decreased myocardial CTSD levels in SCH, and serum CTSD levels were relatively lower in SCH cases. Overall, these results suggest that upregulation of cardiac CTSB and CTSD with age may compensate for the elevated proteolytic demand, and that downregulation of CTSD is potentially linked to SCH. OPEN ACCESS Citation: Kakimoto Y, Sasaki A, Niioka M, Kawabe N, Osawa M (2020) Myocardial cathepsin D is downregulated in sudden cardiac death. PLoS ONE 15(3): e0230375. https://doi.org/10.

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Section: Plos Onesupporting

confidence: 93%

Myocardial cathepsin D is downregulated in sudden cardiac death

et al. 2020

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“…If the cellular machinery does not readily degrade oxidatively damaged proteins, consequences are the accumulation of aggregates and cross-linking of the aggregates´components eventually leading to the formation of large proteinaceous aggregates [77,79]. While protein aggregates are widely known for their pathophysiological role in neurodegenerative diseases their role in cardiovascular diseases and aging has become more apparent only in recent years [80][81][82][83].…”

Section: Protein Degradation Triggered By Oxidative Damagementioning

confidence: 99%

“…The highly oxidized aggregates are not only resistant to proteolytic degradation by the proteasome due to their bulky size but can also block the proteasome and thereby inhibit its function [83,91]. An example is the highly oxidized aggregate lipofuscin, which usually accumulates in lysosomes and is associated with aging and disease, being found in especially high abundance in neurodegenerative disorders [82,92]. Lipofuscin is able to block proteasome activity and further decrease the degradation of oxidized proteins [92].…”

Section: Carbonylation (Dnph)mentioning

confidence: 99%

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Irreversible oxidative post-translational modifications in heart disease

Tomin

Schittmayer

Honeder

et al. 2019

Expert Review of Proteomics

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Introduction: Development of specific biomarkers aiding early diagnosis of heart failure is an ongoing challenge. Biomarkers commonly used in clinical routine usually act as readouts of an already existing acute condition rather than disease initiation. Functional decline of cardiac muscle is greatly aggravated by increased oxidative stress and damage of proteins. Oxidative post-translational modifications occur already at early stages of tissue damage and are thus regarded as potential up-coming disease markers. Areas covered: Clinical practice regarding commonly used biomarkers for heart disease is briefly summarized. The types of oxidative post-translational modification in cardiac pathologies are discussed with a special focus on available quantitative techniques and characteristics of individual modifications with regard to their stability and analytical accessibility. As irreversible oxidative modifications trigger protein degradation pathways or cause protein aggregation, both influencing biomarker abundance, a chapter is dedicated to their regulation in the heart.

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“…Lipofuscin is a yellowish-brown pigment composed of highly oxidized proteins, lipids, and metals. Lipofuscin is widely observed in post-mitotic cells, especially in cells with long life spans such as neurons and cardiomyocytes[1,2]. Lipofuscin is often known as the “age pigment” and is considered a hallmark of aging.…”

Section: Introductionmentioning

confidence: 99%

Observation of the Transport and Removal of Lipofuscin from the Mouse Myocardium using Transmission Electron Microscope

Wang

Changyi

Jia-hua

et al. 2020

Preprint

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This study was performed to investigate whether the lipofuscin formed within cardiomyocytes can be excluded by the myocardial tissue. We have provided indicators that can be used for future studies on anti-aging interventions.In the present study, the heart of a 5-month-old BALB/c mouse was obtained for resin embedding and ultra-thin sectioning. The specimens were observed under a Hitach 7500 transmission electron microscope, and the images were acquired using an XR401 side-insertion device.Lipofuscin granules are found abundantly in myocardial cells. Cardiomyocytes can excrete lipofuscin granules into the myocardial interstitium using capsule-like protrusions that are formed on the sarcolemma. These granules enter the myocardial interstitium and can be de-aggregated to form “membrane-like garbage”, which can pass from the myocardial stroma into the lumen of the vessel through its walls in the form of soluble fine particles through diffusion or endocytosis of capillaries. Smaller lipofuscin granules can pass through the walls of the vessels and enter the blood vessel lumen through the active transport function of the capillary endothelial cells. When the extended cytoplasmic end of macrophages and fibroblasts fuse with the endothelial cells, the lipofuscin granules or clumps found in the cells of the myocardial interstitium are transported to the capillary walls, and then, they are released into the lumen of the blood vessel by the endothelial cells.The myocardial tissues of mice have the ability to eliminate the lipofuscin produced in the cardiomyocytes into the myocardial blood circulation. Although there are several mechanisms through which the myocardial tissues release lipofuscin into the bloodstream, it is mainly carried out in the form of small, fine, soluble, continuous transport.

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Myocardial lipofuscin accumulation in ageing and sudden cardiac death

Cited by 67 publications

References 41 publications

Myocardial cathepsin D is downregulated in sudden cardiac death

Myocardial cathepsin D is downregulated in sudden cardiac death

Irreversible oxidative post-translational modifications in heart disease

Observation of the Transport and Removal of Lipofuscin from the Mouse Myocardium using Transmission Electron Microscope

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