Cardiac ischemia on-a-chip to investigate cellular and molecular response of myocardial tissue under hypoxia

Veldhuizen, Jaimeson; Chavan, Rohidas; Moghadas, Babak; Park, Jin G.; Kodibagkar, Vikram D.; Migrino, Raymond Q.; Nikkhah, Mehdi

doi:10.1016/j.biomaterials.2021.121336

Cited by 45 publications

(39 citation statements)

References 72 publications

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“…Physiological hypoxia refers to the environment with relatively low oxygen concentration in normal embryonic development and brain tissue, which is essential for the exercise of the normal functions (Taylor and Colgan 2017 ). While the disturbance of normal oxygen supply leads to a series of diseases (Hao et al 2022 ; Veldhuizen et al 2021 ). In the process of excessive synovium hyperplasia, severe hypoxia of local tissue due to excessive proliferation is one of the important characteristics of rheumatoid arthritis (RA) joint microenvironment (Jiang et al 2021 ; Guo and Chen 2020 ).…”

Section: Introductionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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Background Hypoxia is one of the important characteristics of synovial microenvironment in rheumatoid arthritis (RA), and plays an important role in synovial hyperplasia. In terms of cell survival, fibroblast-like synovial cells (FLSs) are relatively affected by hypoxia. In contrast, fibroblast-like synovial cells from patients with RA (RA-FLSs) are particularly resistant to hypoxia-induced cell death. The purpose of this study was to evaluate whether fibroblast-like synovial cells in patients with osteoarthritis (OA-FLSs) and RA-FLSs have the same adaptation to hypoxia. Methods CCK-8, flow cytometry and BrdU were used to detect the proliferation of OA-FLSs and RA-FLSs under different oxygen concentrations. Apoptosis was detected by AV/PI, TUNEL and Western blot, mitophagy was observed by electron microscope, laser confocal microscope and Western blot, the state of mitochondria was detected by ROS and mitochondrial membrane potential by flow cytometry, BNIP3 and HIF-1α were detected by Western blot and RT-qPCR. The silencing of BNIP3 was achieved by stealth RNA system technology. Results After hypoxia, the survival rate of OA-FLSs decreased, while the proliferation activity of RA-FLSs further increased. Hypoxia induced an increase in apoptosis and inhibition of mitophagy in OA-FLSs, but not in RA-FLSs. Hypoxia led to a more lasting adaptive response. RA-FLSs displayed a more significant increase in the expression of genes transcriptionally regulated by HIF-1α. Interestingly, they showed higher BNIP3 expression than OA-FLSs, and showed stronger mitophagy and proliferation activities. BNIP3 siRNA experiment confirmed the potential role of BNIP3 in the survival of RA-FLSs. Inhibition of BNIP3 resulted in the decrease of cell proliferation, mitophagy and the increase of apoptosis. Conclusion In summary, RA-FLSs maintained intracellular redox balance through mitophagy to promote cell survival under hypoxia. The mitophagy of OA-FLSs was too little to maintain the redox balance of mitochondria, resulting in apoptosis. The difference of mitophagy between OA-FLSs and RA-FLSs under hypoxia is mediated by the level of BNIP3 expression.

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Section: Introductionmentioning

confidence: 99%

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

Deng

Wang

et al. 2022

Mol Med

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“…The H9c2 cell line is derived from the rat embryonic heart, which has similar electrophysiological and biochemical characteristics of cardiomyocytes (Fang, Luo, & Luo, 2018). Ischemia directly causes hypoxic damage to cardiomyocytes, resulting in apoptosis, structural changes and functional decline, which are closely associated with a variety of diseases (Munoz-Sanchez & Chanez-Cardenas, 2019;Veldhuizen et al, 2022). CoCl 2 is a common chemical drug used to induce hypoxic injury because of its ease of use and stable physicochemical properties (Munoz-Sanchez & Chanez-Cardenas, 2019).…”

Section: Discussionmentioning

confidence: 99%

The cardioprotective effects and mechanisms of naringenin in myocardial ischemia based on network pharmacology and experiment verification

Yang

Chen

et al. 2022

Front. Pharmacol.

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Naringenin (Nar) is a natural flavonoid extracted from citrus fruits with abundant pharmacological properties against cardiac diseases, but existing studies are unsystematic and scattered. The present research systematically investigates the mechanism of action of Nar in the treatment of myocardial ischemia (MI). Network pharmacology was used to analyze the relevant targets of Nar against MI as well as the biological mechanisms. The protective effect of Nar was initially assessed in H9c2 cells induced by CoCl2. In acutely isolated rat cardiomyocytes, Nar was further explored for effects on L-type Ca2+ currents, cell contractility and Ca2+ transients by using patch-clamp technique and Ion Optix system. Network pharmacology analysis indicated that Nar improved apoptosis, mitochondrial energy metabolism, inflammation and oxidative stress. Experimental validation demonstrated that Nar decreased ROS and MDA levels and increased antioxidant activity (e.g., GSH-PX, SOD, and CAT), mitochondrial membrane potential, ATP and Ca2+-ATPase contents. Nar also markedly reduced inflammatory factor levels, apoptosis, and intracellular Ca2+ concentrations in H9c2 cells. Based on the experimental results, it is speculated that Ca2+ signals play an essential role in the process of Nar against MI. Thus, we further confirmed that Nar significantly inhibited the L-type Ca2+ currents, contractility and Ca2+ transients in acutely isolated cardiomyocytes. The inhibition of Ca2+ overload by Nar may be a novel cardioprotective mechanism. The present study may serve as a basis for future clinical research, and Nar as a Ca2+ channel inhibitor may provide new perspectives for the treatment of myocardial ischemic diseases.

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“…Human-induced pluripotent stem cells (hiPSCs; IMR90–4) were obtained from WiCell. The differentiation was based on the previous published method of modulation of Wnt/β-catenin signaling with slight modifications. − hiPSCs were maintained on Matrigel-coated plates in mTeSR1 medium that was changed every 24h. The hiPSCs were passaged at around 80% confluence.…”

Section: Methodsmentioning

confidence: 99%

Passive and Flexible Wireless Electronics Fabricated on Parylene/PDMS Substrate for Stimulation of Human Stem Cell-Derived Cardiomyocytes

et al. 2022

Self Cite

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In this paper, we report the development of a wireless, passive, biocompatible, and flexible system for stimulation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMS). Fabricated on a transparent parylene/PDMS substrate, the proposed stimulator enables real-time excitation and characterization of hiPSC-CMs cultured on-board. The device comprises a rectenna operating at 2.35 GHz which receives radio frequency (RF) energy from an external transmitter and converts it into DC voltage to deliver monophasic stimulation. The operation of the stimulator was primarily verified by delivering monophasic voltage pulses through gold electrodes to hiPSC-CMs cultured on the Matrigel-coated substrates. Stimulated hiPSC-CMs beat in accordance with the monophasic pulses when delivered at 0.5, 1, and 2 Hz pulsing frequency, while no significant cell death was observed. The wireless stimulator could generate monophasic pulses with an amplitude of 8 V at a distance of 15 mm. These results demonstrated the proposed wireless stimulator’s efficacy for providing electrical stimulation to engineered cardiac tissues. The proposed stimulator will have a wide application in tissue engineering where a fully wireless stimulation of electroconductive cells is needed. The device also has potential to be employed as a cardiac stimulator by delivering external stimulation and regulating the contractions of cardiac tissue.

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Cardiac ischemia on-a-chip to investigate cellular and molecular response of myocardial tissue under hypoxia

Cited by 45 publications

References 72 publications

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

The cardioprotective effects and mechanisms of naringenin in myocardial ischemia based on network pharmacology and experiment verification

Passive and Flexible Wireless Electronics Fabricated on Parylene/PDMS Substrate for Stimulation of Human Stem Cell-Derived Cardiomyocytes

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