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Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy.

ABSTRACT: Current approaches in myocardial infarction treatment are limited by low cellular oxidative stress resistance, reducing the long-term survival of therapeutic cells. Here we develop a liquid-crystal substrate with unique surface properties and mechanical responsiveness to produce size-controllable cardiospheres that undergo pyroptosis to improve cellular bioactivities and resistance to oxidative stress. We perform RNA sequencing and study cell metabolism to reveal increased metabolic levels and improved mitochondrial function in the preconditioned cardiospheres. We test therapeutic outcomes in a rat model of myocardial infarction to show that cardiospheres improve long-term cardiac function, promote angiogenesis and reduce cardiac remodeling during the 3-month observation. Overall, this study presents a promising and effective system for preparing a large quantity of functional cardiospheres, showcasing potential for clinical application.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10545739 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy.

Wang Yingwei Y Li Qi Q Zhao Jupeng J Chen Jiamin J Wu Dongxue D Zheng Youling Y Wu Jiaxin J Liu Jie J Lu Jianlong J Zhang Jianhua J Wu Zheng Z

Nature communications 20231002 1

Current approaches in myocardial infarction treatment are limited by low cellular oxidative stress resistance, reducing the long-term survival of therapeutic cells. Here we develop a liquid-crystal substrate with unique surface properties and mechanical responsiveness to produce size-controllable cardiospheres that undergo pyroptosis to improve cellular bioactivities and resistance to oxidative stress. We perform RNA sequencing and study cell metabolism to reveal increased metabolic levels and i ...[more]

PMID: 37783697

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Project description:AimsMyocardial infarction (MI) is one of the serious diseases with great mortality over the world. Myocardial mitochondrial oxidative stress has been implicated as a key player in MI. The histidine triad nucleotide-binding protein 2 (HINT2) is a nucleotide hydrolase and transferase located in mitochondria. HINT2 has multiple functions such as regulating mitochondrial lipid metabolism and respiration and glucose homeostasis. Although HINT2 has been shown to protect against MI, the underlying mechanisms were not fully elucidated. In this study, the effects of HINT2 on oxidative stress during MI were explored.Methods and resultsMI mouse models in both wild-type and HINT2-deficient mice were established. The expression of HINT2 in HINT2-deficient mice was determined by quantitative real-time PCR and western blot. The levels of oxidative stress were measured, including the levels of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH). The myocardial functions, as indicated by left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), were monitored. Both mRNA and protein expressions of HINT2 in the myocardial tissues were significantly down-regulated in MI mice starting at 6 h post-MI. MI induced oxidative stress 6 h post-MI in myocardial tissues of wild-type mice, as suggested by the enhanced MDA and NO levels and decreased SOD and GSH levels. The expression of HINT2 was negatively correlated to the MDA and NO levels and positively correlated to the SOD and GSH levels. HINT2-deficient MI mice had significantly elevated levels of MDA and NO and significantly decreased levels of SOD and GSH when compared with wild-type MI mice. HINT2-deficient MI mice had higher LVEDD and LVESD and lower LVEF and LVFS compared with wild-type MI mice, indicating that HINT2 deficiency exacerbated myocardial dysfunction.ConclusionsHINT2 deficiency causes deteriorative oxidative stress in MI mice, leading to exacerbated myocardial dysfunction.

Project description:BackgroundCardiosphere-derived stem cell (CDC) transplantation can improve global left ventricular ejection fraction (LVEF) after myocardial infarction (MI). The aim of this study was to examine the effects of CDC transplantation on regional function and dyssynchrony after MI.MethodsTwo million rat CDCs (n = 7) or phosphate-buffered saline (n = 7) was injected into the infarct regions of Wistar Kyoto rats. Infarct size and CDC localization were evaluated by positron emission tomography (n = 7). Two-dimensional and strain echocardiography were performed at 1 and 4 weeks after MI. LVEF, circumferential strain, and time to peak circumferential strain were measured in the basal and apical short-axis views. Dyssynchrony was defined as the maximal difference of time to peak circumferential strain of opposing segments in each short-axis view. Engraftment was measured by quantitative polymerase chain reaction.ResultsPositron emission tomography revealed that infarct size was 15.4 ± 3.6% of the left ventricle and that CDCs were localized to the infarct and border zone. CDC transplantation improved mean LVEF (45 ± 8% to 52 ± 7%, P = .02), mean circumferential strain (-7 ± 2% to -10 ± 1%, P = .02), and mean dyssynchrony (45 ± 10 to 28 ± 11 m sec, P = .04) of the infarct/peri-infarct zone from 1 to 4 weeks after MI, despite CDC engraftment of only 2.4 ± 3%. In contrast, mean LVEF (48 ± 5% to 40 ± 4%, P = .03) and mean circumferential strain (-8 ± 2% to -7 ± 1%, P = .02) of the infarcted region deteriorated, with no significant change in dyssynchrony (42 ± 12 vs 46 ± 13 m sec, P = .60) in the saline group during the same time period. Change in LVEF was correlated with change in circumferential strain (r = -0.8, P = .002) and dyssynchrony (r = 0.6, P = .02) of the infarct/peri-infarct region at 4 weeks after MI.ConclusionsCDC therapy enhanced LVEF by improving circumferential strain and decreasing dyssynchrony of the infarct/peri-infarct region at 4 weeks, but not 1 week, after MI. Cellular resynchronization therapy using CDCs may be an alternative to traditional electrical cellular resynchronization therapy in post-MI dyssynchrony.

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Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy.

Publications

Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy.

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