Interaction of ubisemiquinone with a paramagnetic component in heart tissue.

The strategy of heart tissue engineering is simple enough: first remove all the cells from a organ then take the protein scaffold left behind and repopulate it with stem cells immunologically matched to the patient in need. While various suc- cessful methods for decellularization have been developed, and the feasibility of using decellularized whole hearts and extracellular matrix to support cells has been demonstrated, the reality of creating whole hearts for transplantation and of clinical application of decellularized extracellular matrix-based scaffolds will require much more research. For example, further investigations into how lineage-restricted progenitors repopulate the decellularized heart and differentiate in a site-specific manner into different populations of the native heart would be essential. The scaffold heart does not have to be human. Pig hearts carries all the essential components of the extracellular matrix. Through trial and error, scaling up the concentration, timing and pressure of the detergents, researchers have refined the decellularization process on hundreds of hearts and other organs, but this is only the first step. Further, the framework must be populated with human cells. Most researchers in the field use a mixture of two or more cell types, such as endothelial precursor cells to line blood vessels and muscle progenitors to seed the walls of the chambers. The final challenge is one of the hardest: vasculariza- tion, placing a engineered heart into a living animal, integration with the recipient tissue, and keeping it beating for a long time. Much remains to be done before a bioartificial heart is available for transplantation in humans.

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Resveratrol Protects Cardiac Tissue in Experimental Malignant Hypertension Due to Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22095006 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5006

Author(s):

Jelica Grujić-Milanović ◽

Vesna Jaćević ◽

Zoran Miloradović ◽

Djurdjica Jovović ◽

Ivica Milosavljević ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Diseases ◽

Cardiac Tissue ◽

Morphological Changes ◽

Chronic Administration ◽

Heart Tissue ◽

Severe Form ◽

Malignant Hypertension ◽

Experimental Hypertension ◽

Resveratrol Treatment

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

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Menthol exposure induces reversible cardiac depression and reduces lipid peroxidation in the heart tissue of tambaqui Colossoma macropomum

Aquaculture ◽

10.1016/j.aquaculture.2021.736847 ◽

2021 ◽

Vol 541 ◽

pp. 736847

Author(s):

Sildiane Martins Cantanhêde ◽

Lílian Lund Amado ◽

Brenda Maria P. Alho da Costa ◽

Luis André L. Barbas ◽

Marcelo Ferreira Torres ◽

...

Keyword(s):

Lipid Peroxidation ◽

Heart Tissue ◽

Colossoma Macropomum ◽

Cardiac Depression

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Circulating miR-146a as a possible candidate biomarker in the indeterminate phase of Chagas disease

Biological Research ◽

10.1186/s40659-021-00345-3 ◽

2021 ◽

Vol 54 (1) ◽

Author(s):

Martha Alicia Ballinas-Verdugo ◽

Rogelio Frank Jiménez-Ortega ◽

Eduardo Martínez-Martínez ◽

Nancy Rivas ◽

Erick Abraham Contreras-López ◽

...

Keyword(s):

Chagas Disease ◽

Extracellular Vesicles ◽

Bioinformatics Analysis ◽

Chronic Phase ◽

Heart Tissue ◽

Detailed Knowledge ◽

Total Plasma ◽

Chain Reaction ◽

Polymerase Chain ◽

Relevant Finding

Abstract Background Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-β signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. Results Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. Conclusions The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

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Hexagonal boron nitride nanoparticles trigger oxidative stress by modulating thiol/disulfide homeostasis

Human & Experimental Toxicology ◽

10.1177/09603271211002892 ◽

2021 ◽

pp. 096032712110028

Author(s):

F Kar ◽

İ Söğüt ◽

C Hacıoğlu ◽

Y Göncü ◽

H Şenturk ◽

...

Keyword(s):

Oxidative Stress ◽

Boron Nitride ◽

Hexagonal Boron Nitride ◽

Chemical Properties ◽

Heart Tissue ◽

Albino Rats ◽

Dependent Manner ◽

Tissue Samples ◽

Boron Nitride Nanoparticles

Background: Hexagonal boron nitride nanoparticles (hBN NPs) are encouraging nanomaterials with unique chemical properties in medicine and biomedical fields. Until now, the optimal hBN NP’s dosage and biochemical mechanism that can be used for in vivo systems has not been fully revealed. The main aim of this article is to reveal characteristics, serum and tissue interactions and any acute cytotoxic effect of different dose of hBN NPs for the first time. Methods: hBN NPs at concentrations varying between 50–3200 µg/kg was administered by intravenous injection to Wistar albino rats (n = 80) divided into seven dosage and control groups. Blood and tissue samples were taken after 24 hours. Results: Our findings suggested that higher doses hBN NPs caused oxidative stress on the serum of rats dose-dependently. However, hBN NPs did not affect thiol/disulfide homeostasis on kidney, liver, spleen, pancreas and heart tissue of rats. Furthermore, hBN NPs increased serum disulfide formation by disrupting the thiol/disulfide balance in rats. Also, LOOH and MPO levels increased at high doses, while CAT levels decreased statistically. Conclusion: The results revealed that hBN NPs induce oxidative stress in a dose-dependent manner by modulating thiol/disulfide homeostasis in rats at higher concentrations

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

Micromachines ◽

10.3390/mi12040386 ◽

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.

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Development of matured hiPSCs-derived 3D cardiac tissue using ERR gamma agonist and mechanical stress and application for Hypertrophic Cardiomyopathy (HCM) model

European Heart Journal ◽

10.1093/ehjci/ehaa946.3668 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

Y Fujiwara ◽

K Deguchi ◽

Y Naka ◽

M Sasaki ◽

T Nishimoto ◽

...

Keyword(s):

Mitochondrial Dna ◽

Hypertrophic Cardiomyopathy ◽

Mechanical Stress ◽

Cell Size ◽

Dna Content ◽

Disease Model ◽

Heart Tissue ◽

Funding Source ◽

Mitochondrial Dna Content ◽

Mechanical Stretching

Abstract Introduction Tissue engineering using human induced pluripotent stem cells-derived cardiomyocytes (hiPSCs-CMs) is one of the potential tools to replicate human heart in vitro. Although there are many publications on 3 dimensional (3D) heart tissues (1), these tissues show fetal like phenotypes. For that reason, several maturation methods such as electrical stimulation and mechanical stress have been investigated (2, 3). However, these methods have been inadequate in differentiating fetal like phenotype tissue from adult tissues. Previously, we identified a novel compound, T112, which induced hiPSCs-CMs maturation from approximately 9,000 compounds using Troponin I1-EmGFP and Troponin I3-mCherry double reporter hiPSCs-CMs. This compound enhanced morphological and metabolic maturation of hiPSCs-CMs via estrogen-rerated receptor gamma activation Purpose We hypothesized that our novel compound, T112, in combination with mechanical stress could result in further maturation of 3D heart tissue. Therefore, our specific aim is to develop a novel maturation method applicable to genetic disease model of HCM using 3D heart tissue combined with T112. Methods We constructed 3D heart tissue mixed with fibroblast and double reporter hiPSCs-CMs by the hydrogel methods using Flex cell system®. We added T112 with or without mechanical stretching to 3D tissue from 7 to 15 days after 3D heart tissue was constructed. Then we measured maturation related phenotype such as sarcomere gene expression, mitochondrial DNA content and cell size. Results Similar to hiPSCs-CM, the addition of T112 to the constructed 3D heart tissue significantly increased TNNI3 mRNA compared to that of DMSO. Furthermore, T112 treated 3D heart tissue showed increased cell size and oblong shape. Next, in order to promote more maturation of 3D heart tissue, we performed mechanical stretching with the addition of T112. The combination of T112 with mechanical stretching showed higher expression of mCherry, a reporter protein for TNNI3 expression, and higher isotropy of sarcomere alignment in 3D heart tissue than that with the static condition. Furthermore, 3D heart tissue in the treatment of T112 with or without mechanical stretching showed higher mitochondrial DNA content compared to the respective DMSO controls. Interestingly, we applied this combination method to hiPSCs carrying MYH7 R719Q mutation which is known to cause hypertrophic cardiomyopathy, and the 3D heart tissue composed of cardiomyocytes derived from mutant iPSCs demonstrated increased sarcomere disarray compared to isogenic wild-type 3D heart tissue. Conclusion These results suggest that the combination of T112 and mechanical stretching promotes metabolic and structural maturation of 3D heart tissue and would be useful for creating a HCM disease model. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): T-CiRA project, Takeda Pharmaceutical Company Limited

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Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals?

Basic Research in Cardiology ◽

10.1007/s00395-021-00875-7 ◽

2021 ◽

Vol 116 (1) ◽

Cited By ~ 1

Author(s):

Maaike te Lintel Hekkert ◽

Gary Newton ◽

Kathryn Chapman ◽

Rehan Aqil ◽

Robert Downham ◽

...

Keyword(s):

Stem Cell ◽

Infarct Size ◽

Clinical Success ◽

Heart Tissue ◽

Balloon Occlusion ◽

Large Mammals ◽

Preclinical Trial ◽

Large Mammal ◽

Lv Mass ◽

Technical Issues

AbstractReducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.

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Mitochondrial P2X7 receptor localization modulates energy metabolism enhancing physical performance

Function ◽

10.1093/function/zqab005 ◽

2021 ◽

Author(s):

Alba Clara Sarti ◽

Valentina Vultaggio-Poma ◽

Simonetta Falzoni ◽

Sonia Missiroli ◽

Anna Lisa Giuliani ◽

...

Keyword(s):

Energy Metabolism ◽

Physical Fitness ◽

P2x7 Receptor ◽

Human Fibroblasts ◽

Atp Synthesis ◽

Heart Tissue ◽

Mitochondrial Potential ◽

Mitochondrial Energy Metabolism ◽

Microglia Cell ◽

Basal Expression

Abstract Basal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, ATP synthesis and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack a) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca2+ level, b) modifies expression pattern of oxidative phosphorylation (OxPhos) enzymes, and c) severely affects cardiac performance. Hearts from P2rx7-deleted versus WT mice are larger, heart mitochondria smaller, and stroke volume (SV), ejection fraction (EF), fractional shortening (FS) and cardiac output (CO), are significantly decreased. Accordingly, physical fitness of P2X7R-null mice is severely reduced. Thus, the P2X7R is a key modulator of mitochondrial energy metabolism and a determinant of physical fitness.

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