Abstract P340: Histone Methyltransferase Smyd1a Protects Heart From Ischemic Injury By Regulating Mitochondrial Respiration

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Marta Szulik ◽  
Steven Valdez ◽  
Maureen Walsh ◽  
Ryan Bia ◽  
Kathryn Davis ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Transcriptional Control ◽  
Cardiac Tissue ◽  
Ischemic Injury ◽  
Protective Role ◽  
Atp Production ◽  
Histone Lysine Methyltransferase ◽  
Permanent Occlusion ◽  
Consumption Rates

SMYD1a, a myosin-specific histone lysine methyltransferase, plays a major role in regulating disease-induced remodeling in the adult heart. Previously, we demonstrated that the inducible loss of this chromatin-bound enzyme is sufficient to induce cardiac hypertrophy and failure in vivo , which is preceded by downregulation of mitochondrial proteins involved in oxidative phosphorylation (OXPHOS), and reduction of mitochondrial respiration capacity. However, our most recent data in transgenic mice (TG) displaying inducible, cardiomyocyte-specific overexpression of SMYD1a show that these mice are protected from ischemic injury after permanent occlusion (PO) of the LAD manifested by reduced infarct size and cardiac dysfunction compared to littermate controls (WT), suggesting that SMYD1 plays a protective role in the heart and mitigates disease-induced remodeling. Additionally, global proteomic evaluation of cardiac tissue from TG mice showed unique expression of metabolic enzymes, including proteins from the electron transport chain, and our high-resolution mitochondrial respirometry analysis showed that overexpression of SMYD1a leads to increased oxygen consumption rates through Complex I and II. To further asses OXPHOS efficiency in TG mice we subjected them to permanent occlusion of the LAD and evaluated ATP production rates in isolated mitochondria from TG and WT mice, by measuring the molar amount of ATP produced per mole of atomic oxygen consumed (known as ATP:O ratio). Interestingly, we observed a significant increase in ATP:O ratio in TG mice 24h after PO suggesting that they are much more efficient at producing ATP. Finally, we show that the global regulation of mitochondrial respiration in TG mice occurs through transcriptional control of Ppargc1α . Our results confirm that cardiac expression of Ppargc1α was significantly reduced in WT mice (48h after PO) but maintained at basal levels in TG mice, which also corroborated with our ChIP-qPCR data showing SMYD1a binding to the Ppargc1α promoter and regulating its expression. Overall, these results show that SMYD1a can mitigate ischemic injury and adverse remodeling in the adult myocardium, which occurs through Ppargc1α expression and regulation of cardiac energetics and metabolism.

scholarly journals Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells

Gut ◽  
2019 ◽  
Vol 69 (6) ◽  
pp. 1104-1115 ◽  
Author(s):  
Zhen Dai ◽  
Guangqi Song ◽  
Asha Balakrishnan ◽  
Taihua Yang ◽  
Qinggong Yuan ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Progenitor Cells ◽  
Liver Diseases ◽  
Transcriptional Control ◽  
Cell Types ◽  
Protective Role ◽  
Chronic Liver ◽  
Chronic Liver Diseases ◽  
Differentiation Factor

ObjectiveLiver fibrosis and cirrhosis resulting from chronic liver injury represent a major healthcare burden worldwide. Growth differentiation factor (GDF) 11 has been recently investigated for its role in rejuvenation of ageing organs, but its role in chronic liver diseases has remained unknown. Here, we investigated the expression and function of GDF11 in liver fibrosis, a common feature of most chronic liver diseases.DesignWe analysed the expression of GDF11 in patients with liver fibrosis, in a mouse model of liver fibrosis and in hepatic stellate cells (HSCs) as well as in other liver cell types. The functional relevance of GDF11 in toxin-induced and cholestasis-induced mouse models of liver fibrosis was examined by in vivo modulation of Gdf11 expression using adeno-associated virus (AAV) vectors. The effect of GDF11 on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)+ liver progenitor cells was studied in mouse and human liver organoid culture. Furthermore, in vivo depletion of LGR5+ cells was induced by injecting AAV vectors expressing diptheria toxin A under the transcriptional control of Lgr5 promoter.ResultsWe showed that the expression of GDF11 is upregulated in patients with liver fibrosis and in experimentally induced murine liver fibrosis models. Furthermore, we found that therapeutic application of GDF11 mounts a protective response against fibrosis by increasing the number of LGR5+ progenitor cells in the liver.ConclusionCollectively, our findings uncover a protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.

scholarly journals The Role of Dietary Saturated Fat in Associations between Exposure to Ambient Fine Particulate Matter and Mitochondrial Respiratory Functions in Circulating Platelets

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 523-523
Author(s):  
Wan Shen ◽  
Hao Chen ◽  
James Samet ◽  
Haiyan Tong
Keyword(s):  
Oxygen Consumption ◽  
Mitochondrial Respiration ◽  
Saturated Fatty Acids ◽  
Fine Particulate Matter ◽  
Saturated Fat ◽  
Basal Respiration ◽  
Mitochondrial Oxygen Consumption ◽  
Atp Production ◽  
Consumption Rates ◽  
Mitochondrial Respiratory

Abstract Objectives Exposure to ambient fine particulate matter (PM2.5) is associated with platelet activation and increased mitochondrial respiration. The impact of dietary saturated fat on the circulating platelets is not understood. This project aimed to determine whether dietary saturated fatty acids moderate mitochondrial respiratory function in circulating platelets after short-term exposure to PM2.5. Methods Platelets were isolated from 22 healthy male volunteers (mean age ± SD, 37 ± 8.2) in a panel study and measured for mitochondrial oxygen consumption rates using an extracellular flux analyzer. Intakes of saturated fat were determined from 24 hr dietary recalls the day before the assay. Daily ambient PM2.5 concentrations during the study period were obtained from ambient air quality monitoring stations. Data were fitted with a moderation model, where the level of ambient PM2.5 was the independent variable, saturated fat intake was the moderator, and mitochondrial respiratory functions in circulating platelets were the dependent variables. Results After controlling for age, dietary consumption of saturated fat moderated the mitochondrial oxygen consumption rates of non-mitochondrial respiration, basal respiration, maximum respiration, ATP production, and spare respiratory capacity after exposure to ambient PM2.5 with 2 days lag. Specifically, the negative associations between the above mentioned mitochondrial respiratory measurements and PM2.5 levels reached statistical significance (95% Confident Intervals did not include 0) in subjects with a high intake of total saturated fat. Further, results for individual saturated fatty acid showed similar patterns, specifically that negative association between mitochondrial oxygen consumption rates of non-mitochondrial respiration, basal respiration and ATP production and levels of exposed PM2.5 was moderated by intakes of short-chain (C4:0), medium-chain (C6:0, C8:0, C10:0, C12:0), long-chain (C14:0, C16:0) saturated fatty acids. Conclusions Taken together, these preliminary findings suggest that consumption of saturated fat moderates platelet mitochondrial respiration after exposure to PM2.5.  THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY. Funding Sources This project was supported by the U.S. EPA Intramural Research Program.

The platelet-derived chemokine CXCL4 exerts protective role in non-alcoholic steatohepatitis (NASH) in vivo

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
HK Drescher ◽  
C Berger ◽  
P Fischer ◽  
ML Berres ◽  
DC Kroy ◽  
...  
Keyword(s):  
Protective Role ◽  
Alcoholic Steatohepatitis

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

scholarly journals Extrinsically Conductive Nanomaterials for Cardiac Tissue Engineering Applications

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 914
Author(s):  
Arsalan Ul Haq ◽  
Felicia Carotenuto ◽  
Paolo Di Nardo ◽  
Roberto Francini ◽  
Paolo Prosposito ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Cardiac Tissue ◽  
Scar Tissue ◽  
Cardiac Tissue Engineering ◽  
Assistive Device ◽  
Long Run ◽  
Fibrotic Scar ◽  
Regeneration Capability ◽  
Conductive Nanomaterials

Myocardial infarction (MI) is the consequence of coronary artery thrombosis resulting in ischemia and necrosis of the myocardium. As a result, billions of contractile cardiomyocytes are lost with poor innate regeneration capability. This degenerated tissue is replaced by collagen-rich fibrotic scar tissue as the usual body response to quickly repair the injury. The non-conductive nature of this tissue results in arrhythmias and asynchronous beating leading to total heart failure in the long run due to ventricular remodelling. Traditional pharmacological and assistive device approaches have failed to meet the utmost need for tissue regeneration to repair MI injuries. Engineered heart tissues (EHTs) seem promising alternatives, but their non-conductive nature could not resolve problems such as arrhythmias and asynchronous beating for long term in-vivo applications. The ability of nanotechnology to mimic the nano-bioarchitecture of the extracellular matrix and the potential of cardiac tissue engineering to engineer heart-like tissues makes it a unique combination to develop conductive constructs. Biomaterials blended with conductive nanomaterials could yield conductive constructs (referred to as extrinsically conductive). These cell-laden conductive constructs can alleviate cardiac functions when implanted in-vivo. A succinct review of the most promising applications of nanomaterials in cardiac tissue engineering to repair MI injuries is presented with a focus on extrinsically conductive nanomaterials.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

scholarly journals Osteocytes as main responders to low-intensity pulsed ultrasound treatment during fracture healing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tatsuya Shimizu ◽  
Naomasa Fujita ◽  
Kiyomi Tsuji-Tamura ◽  
Yoshimasa Kitagawa ◽  
Toshiaki Fujisawa ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Transcriptional Control ◽  
Target Genes ◽  
Pulsed Ultrasound ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity ◽  
Ultrasound Stimulation

AbstractUltrasound stimulation is a type of mechanical stress, and low-intensity pulsed ultrasound (LIPUS) devices have been used clinically to promote fracture healing. However, it remains unclear which skeletal cells, in particular osteocytes or osteoblasts, primarily respond to LIPUS stimulation and how they contribute to fracture healing. To examine this, we utilized medaka, whose bone lacks osteocytes, and zebrafish, whose bone has osteocytes, as in vivo models. Fracture healing was accelerated by ultrasound stimulation in zebrafish, but not in medaka. To examine the molecular events induced by LIPUS stimulation in osteocytes, we performed RNA sequencing of a murine osteocytic cell line exposed to LIPUS. 179 genes reacted to LIPUS stimulation, and functional cluster analysis identified among them several molecular signatures related to immunity, secretion, and transcription. Notably, most of the isolated transcription-related genes were also modulated by LIPUS in vivo in zebrafish. However, expression levels of early growth response protein 1 and 2 (Egr1, 2), JunB, forkhead box Q1 (FoxQ1), and nuclear factor of activated T cells c1 (NFATc1) were not altered by LIPUS in medaka, suggesting that these genes are key transcriptional regulators of LIPUS-dependent fracture healing via osteocytes. We therefore show that bone-embedded osteocytes are necessary for LIPUS-induced promotion of fracture healing via transcriptional control of target genes, which presumably activates neighboring cells involved in fracture healing processes.

scholarly journals Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase

2021 ◽  
Author(s):  
Marco Fiorillo ◽  
Cristian Scatena ◽  
Antonio Giuseppe Naccarato ◽  
Federica Sotgia ◽  
Michael P. Lisanti
Keyword(s):  
Cell Migration ◽  
Treatment Failure ◽  
Atp Synthase ◽  
Atp Depletion ◽  
Multi Drug Resistance ◽  
Gamma Subunit ◽  
Primary Tumors ◽  
Atp Production ◽  
Mitochondrial Atp Synthase

AbstractHere, we provide evidence that high ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anticancer therapy, especially for preventing tumor progression. More specifically, we isolated a subpopulation of ATP-high cancer cells which are phenotypically aggressive and demonstrate increases in proliferation, stemness, anchorage-independence, cell migration, invasion and multi-drug resistance, as well as high antioxidant capacity. Clinically, these findings have important implications for understanding treatment failure and cancer cell dormancy. Using bioinformatic analysis of patient samples, we defined a mitochondrial-related gene signature for metastasis, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). The relationship between ATP5F1C protein expression and metastasis was indeed confirmed by immunohistochemistry. Next, we used MDA-MB-231 cells as a model system to functionally validate these findings. Importantly, ATP-high MDA-MB-231 cells showed a nearly fivefold increase in metastatic capacity in vivo. Consistent with these observations, ATP-high cells overexpressed (i) components of mitochondrial complexes I–V, including ATP5F1C, and (ii) markers associated with circulating tumor cells (CTCs) and metastasis, such as EpCAM and VCAM1. Knockdown of ATP5F1C expression significantly reduced ATP-production, anchorage-independent growth, and cell migration, as predicted. Similarly, therapeutic administration of the FDA-approved drug, Bedaquiline, downregulated ATP5F1C expression in vitro and prevented spontaneous metastasis in vivo. In contrast, Bedaquiline had no effect on the growth of non-tumorigenic mammary epithelial cells (MCF10A) or primary tumors in vivo. Taken together, our results suggest that mitochondrial ATP depletion is a new therapeutic strategy for metastasis prophylaxis, to avoid treatment failure. In summary, we conclude that mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

scholarly journals The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Fangfang Tao ◽  
Yanrong Zhang ◽  
Zhiqian Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cell ◽  
Apoptotic Cell ◽  
Redox Status ◽  
Cancer Therapies ◽  
Bioactive Components ◽  
Atp Production

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.

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