TIR/BB-loop mimetic AS-1 attenuates cardiac ischemia/reperfusion injury via a caveolae and caveolin-3-dependent mechanism

Hu, Yuanyang; Zhang, Meiling; Shen, Xin; Dai, Guoliang; Ren, Danyang; Que, Linli; Ha, Tuanzhu; Li, Chuanfu; Xu, Yong; Ju, Wenzheng; Li, Yuehua

doi:10.1038/srep44638

Cited by 4 publications

(2 citation statements)

References 28 publications

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“…Whole-cell protein lysates were generated using total lysis buffer; nuclear and cytoplasmic protein lysates were generated using buffer A and buffer C as previously described ( 23 ). Both protein isolation reagents were supplemented with complete protease inhibitor cocktail (Roche Diagnostics, USA).…”

Section: Methodsmentioning

confidence: 99%

ECSIT inhibits cell death to increase tumor progression and metastasis via p53 in human breast cancer

Hu¹,

Liu²,

Zhang³

et al. 2022

Transl Cancer Res TCR

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Background Currently, breast cancer has surpassed lung cancer as the most common cancer and the molecular mechanism involved in tumor initiation and metastasis was unclear. Therefore, it is necessary to advance our understanding of tumor progression and metastasis and find out new targets. An evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is involved in the innate immune response and has been shown as tumor suppressors by downregulating nuclear factor-kappa B (NF-κB) pathway. However, the role of ECSIT in the progression and metastasis of human breast cancer remains unknown. Methods We overexpressed ECSIT by transfection of a eukaryotic expression plasmid and constructed a breast cancer cell line with stable knockdown of ECSIT by short hairpin RNA. And we silenced p53 through small interfering RNA. In vivo , we replicated a xenograft mouse model in nude mice. The effects on the proliferation, viability, migration and invasion were studied by 5-ethynyl-2-deoxyuridine, cell counting Kit-8, wound healing and invasion assays. Propidium iodide/Hoechst 33342 staining and cleaved-caspase-3 staining were used to verify cell death. Western blot, immunohistochemistry (IHC) and histological analyses were used to explore the regulatory mechanism of tumor changes. Results We reported the association of ECSIT with human breast cancer. In vitro assays demonstrated that ECSIT promoted MDA-MB-231 cell proliferation (by 66.15%), migration and invasion (by 58.29%). Knockdown of ECSIT significantly decreased cell proliferation (by 38.33%), viability, migration and invasion (by 62.37%), and increased cell death (by 41.1%). The in vivo results further confirmed that knockdown of ECSIT depressed tumorigenicity (by 29.46%) and metastasis (by 76.19%). Mechanistic investigations indicated that silencing of ECSIT could decrease the expression of p65 (by 46.05%), a subunit of NF-κB, and increase p53 protein expression in nuclei (by 89.53%). Moreover, we demonstrated that knockdown of p53 abolished the protection against cell death, which indicated that ECSIT might be involved in breast cancer progression through a p53-dependent pathway. Conclusions Our studies provide new insight into the mechanisms underlying the role of ECSIT as well as a novel target for human breast cancer, and the development of novel ECSIT inhibitors is important for the management of TNBC.

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Section: Methodsmentioning

confidence: 99%

ECSIT inhibits cell death to increase tumor progression and metastasis via p53 in human breast cancer

Hu¹,

Liu²,

Zhang³

et al. 2022

Transl Cancer Res TCR

Self Cite

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“…Several studies suggested that hydrocinnamoyl-L-valyl pyrrolidine (AS-1), a synthetic mimetic of TIR/BB-loop, has protective effects against cardiovascular diseases 17–19 . Our previous studies reported that the application of AS-1 prevented the transverse aortic constriction (TAC)-induced hypertrophy in vivo through blocking the activity of transcription factor NF-κΒ and MAPK activation 18 .…”

Section: Introductionmentioning

confidence: 99%

The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-κB dependent downregulation of miRNA-143

Song

Xie

Wang

et al. 2019

Sci Rep

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Untreated pathological cardiac hypertrophy, which can be caused by sustained systemic hypertension, may lead to heart failure. In the present study, we investigated whether AS-1 had attenuating effects on hypertension-induced cardiac hypertrophy, and whether this process was mediated by the regulation of miRNA-143. To induce the hypertrophic response in vitro , cardiomyocytes were stimulated with Ang II for 24hs. AS-1 administration strongly attenuated Ang II-induced hypertrophic response of cardiomyocytes. Chronical infusion of Ang II via implanted osmotic mini-pump induced increased blood pressure and cardiac hypertrophy in vivo . AS-1 administration attenuated hypertension-induced cardiac hypertrophy by, at least in part, inhibin of MAPK signaling. We observed, for the first time, upregulated expression of miRNA-143 in Ang II-induced cardiomyocytes, and inhibition of miRNA-143 significantly reduced the Ang II-induced hypertrophic responses. Importantly, AS-1 administration diminished the Ang II-induced upregulation of miRNA-143. Overexpression of miRNA-143 abolished the attenuating effects of AS-1 on Ang II-induced hypertrophic response of cardiomyocytes. Additionally, AS-1 administration abrogates Ang II-induced nuclear translocation of p50 NF-κB subunit in hypertrophic cardiomyocytes. Application of NF-κB inhibitor significantly suppressed Ang II-induced upregulation of miRNA-143. Our data suggest a novel mechanism by which AS-1 attenuates Ang II-induced hypertrophic response through downregulation miRNA-143 expression in a NF-κB-dependent manner.

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Pathophysiology and molecular mechanism of caveolin involved in myocardial protection strategies in ischemic conditioning

Zhao¹,

Yang²,

An³

et al. 2022

Biomedicine & Pharmacotherapy

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TIR/BB-loop mimetic AS-1 attenuates cardiac ischemia/reperfusion injury via a caveolae and caveolin-3-dependent mechanism

Cited by 4 publications

References 28 publications

ECSIT inhibits cell death to increase tumor progression and metastasis via p53 in human breast cancer

ECSIT inhibits cell death to increase tumor progression and metastasis via p53 in human breast cancer

The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-κB dependent downregulation of miRNA-143

Pathophysiology and molecular mechanism of caveolin involved in myocardial protection strategies in ischemic conditioning

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