STAT4 regulates cardiomyocyte apoptosis in rat models of diabetic cardiomyopathy

He²,

Front. Cardiovasc. Med.

et al. 2023

Self Cite

Lysine ß-hydroxybutyrylation (kbhb), a novel modification of lysine residues with the ß-hydroxybuty group, is associated with ketone metabolism in numerous species. However, its potential role in diabetes, especially in diabetic cardiomyopathy (DCM), remains largely unexplored. In this study, using affinity enrichment and liquid chromatography-mass spectrometry (LC-MS/MS) method, we quantitatively analyze the kbhb residues on heart tissues of a DCM model rat. A total of 3,520 kbhb sites in 1,089 proteins were identified in this study. Further analysis showed that 336 kbhb sites in 143 proteins were differentially expressed between the heart tissues of DCM and wild-type rats. Among them, 284 kbhb sites in 96 proteins were upregulated, while 52 kbhb sites in 47 proteins were downregulated. Bioinformatic analysis of the proteomic results revealed that these kbhb-modified proteins were widely distributed in various components and involved in a wide range of cellular functions and biological processes (BPs). Functional analysis showed that the kbhb-modified proteins were involved in the tricarboxylic acid cycle, oxidative phosphorylation, and propanoate metabolism. Our findings demonstrated how kbhb is related to many metabolic pathways and is mainly involved in energy metabolism. These results provide the first global investigation of the kbhb profile in DCM progression and can be an essential resource to explore DCM’s pathogenesis further.

Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Proteome-wide analysis of lysine β-hydroxybutyrylation in the myocardium of diabetic rat model with cardiomyopathy

He²,

Front. Cardiovasc. Med.

et al. 2023

Self Cite

“…For example, Li et al showed IL-35 produced anti-in ammatory and antiapoptotic effects on lipopolysaccharide-induced endothelial cell activation by activating STAT4 signaling pathways [56]. A recent study reported that overexpression of STAT4 reduced high glucose-induced apoptosis in the H9C2 cells [57].…”

Section: Discussionmentioning

confidence: 99%

STAT4-Mediated Klotho Up-Regulation Contributes to the Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning via Inhibiting Neuronal Pyroptosis

Liu,

Zhang,

Wang

et al. 2023

Mol Neurobiol

Our previous study has proved that the Klotho up-regulation participated in cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance. However, the exact neuroprotective mechanism of Klotho in CIP remains unclear. We explored the hypothesis that STAT4-mediated Klotho upregulation contributes to the CIP-induced brain ischemic tolerance via inhibiting neuronal pyroptosis. Firstly, the expressions of pyroptosis-associated proteins (i.e., NLRP3, GSDMD, pro-caspase-1, and cleaved caspase-1) in hippocampal CA1 region were determined during the process of brain ischemic tolerance. We found the expression of pyroptosis-associated proteins was signi cantly up-regulated in the ischemic insult (II) group, and showed no signi cant changes in the CIP group. The expression level of each pyroptosisassociated proteins was lower in the CIP + II group than that in the II group. Inhibition of Klotho expression increased the expression of pyroptosis-associated proteins in the CIP + II group and blocked the CIP-induced brain ischemic tolerance. Injection of Klotho protein decreased the expression of pyroptosis-associated proteins in the II group, and protected neurons from ischemic injury. Secondly, the transcription factor STAT4 of Klotho was identi ed by bioinformatic analysis. Double luciferase reporter gene assay and chromatin immunoprecipitation assay showed STAT4 can bind to the site between nt − 881 and -868 on the Klotho promoter region and positively regulates Klotho expression. Moreover, we found CIP signi cantly enhanced the expression of STAT4. Knockdown STAT4 suppressed Klotho upregulation after CIP and blocked the CIP-induced brain ischemic tolerance. Collectively, it can be concluded that STAT4-mediated upregulation of Klotho contributed to the brain ischemic tolerance induced by CIP via inhibiting pyroptosis.

Front. Cardiovasc. Med.

“…Apoptosis is an activity and PCD mediated by gene regulation, which can lead to morphological and biochemical changes, including cell shrinkage, plasma membrane blebbing, chromosome pyknosis, nuclear fragmentation, and DNA banding, and ultimately phagocytose cells by phagosomes (12). A large amount of evidence has confirmed that proper regulation of apoptosis has a profound impact on the process of various CVD (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Pyroptosis is an inflammatory type of programmed cell necrosis, in which cell membrane pores are formed, cells rapidly swell and rupture, and pro-inflammatory factors and cell contents are released (25).…”

Section: Introductionmentioning

confidence: 99%

The crosstalk among autophagy, apoptosis, and pyroptosis in cardiovascular disease

Liu

Bai

Guo

2022

In recent years, the mechanism of cell death has become a hotspot in research on the pathogenesis and treatment of cardiovascular disease (CVD). Different cell death modes, including autophagy, apoptosis, and pyroptosis, are mosaic with each other and collaboratively regulate the process of CVD. This review summarizes the interaction and crosstalk of key pathways or proteins which play a critical role in the entire process of CVD and explores the specific mechanisms. Furthermore, this paper assesses the interrelationships among these three cell deaths and reviews how they regulate the pathogenesis of CVD. By understanding how these three cell death modes go together we can learn about the pathogenesis of CVD, which will enable us to identify new targets for preventing, controlling, and treating CVD. It will not only reduce mortality but also improve the quality of life.