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Rosiglitazone reduces diabetes angiopathy by inhibiting mitochondrial dysfunction dependent on regulating HSP22 expression.

ABSTRACT: The effects of rosiglitazone (RSG) in patients with type 2 diabetes mellitus (T2DM) remain controversial. Here, we first used network pharmacology to identify the common targets of RSG in the treatment of diabetes angiopathy (DA). Enrichment analysis found that the common genes were involved in the inflammatory response, leukocyte cell-cell adhesion, mitochondrion organization and oxidative stress. Our previous research confirmed that heat shock protein 22 (HSP22) suppresses diabetes-induced endothelial activation and injury by inhibiting mitochondrial reactive oxygen species (mtROS) formation and dysfunction. We then constructed HSP22 knockout mice with T2DM to investigate whether RSG protected the vascular endothelium by upregulating HSP22. Our study suggested that RSG reduced vascular endothelial cell activation and injury by decreasing monocyte adhesion and cytokine secretion and simultaneously upregulating HSP22 expression. Mechanistically, RSG inhibited mitochondrial oxidative stress and dysfunction by regulating PPAR-γ in a manner partially dependent on expression of HSP22, resulting in reduced DA.

SUBMITTER: Yu L

PROVIDER: S-EPMC10031002 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Rosiglitazone reduces diabetes angiopathy by inhibiting mitochondrial dysfunction dependent on regulating HSP22 expression.

Yu Lingling L Chen Shengsong S Liang Qian Q Huang Chahua C Zhang Weifang W Hu Longlong L Yu Yun Y Liu Liang L Cheng Xiaoshu X Bao Huihui H

iScience 20230213 4

The effects of rosiglitazone (RSG) in patients with type 2 diabetes mellitus (T2DM) remain controversial. Here, we first used network pharmacology to identify the common targets of RSG in the treatment of diabetes angiopathy (DA). Enrichment analysis found that the common genes were involved in the inflammatory response, leukocyte cell-cell adhesion, mitochondrion organization and oxidative stress. Our previous research confirmed that heat shock protein 22 (HSP22) suppresses diabetes-induced end ...[more]

PMID: 36968091

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Project description:BackgroundThe high morbidity and mortality rate of coronary heart disease poses a serious threat to human health. Atherosclerosis, a chronic inflammation of the blood vessel wall, is a significant pathological process leading to coronary heart disease. Macrophage inflammation plays a crucial role in the occurrence and development of atherosclerosis.MethodsMacrophage inflammation model was constructed by lipopolysaccharide (LPS), and macrophages were treated with Celastrol at different concentrations (0, 0.1, 1, 10, 100 ng/mL) and different time points (0, 1, 3, 6, 12 h). Real-time quantitative PCR (qPCR) and Western Blot were used to detect the expression of Nur77 mRNA and protein. Macrophages were then pretreated with 100 nmol/L tripterine for 40min and co-cultured with 100 ng/mL LPS. The expression levels of inflammatory factors and chemokines, phosphorylation of phospho-dynamin-related protein 1 (p-Drp1) at Ser637 and expression of mitochondrial fusion protein mitochondrial fusion protein mitofusin-2 (Mfn2) were detected by qPCR, Western blot and ELISA, respectively. The changes of mitochondrial membrane potential were detected by JC-1 probe.Results100 nmol/L Celastrol can significantly inhibit LPS-induced inflammatory responses and down-regulate the expression levels of cytokines such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), chemokines (CCL-2, and CXCL-10), as well as chemokines. And Celastrol could regulate mitochondrial fission and fusion by promoting the phosphorylation of the Drp1 at the Ser637 site, thereby inhibiting mitochondrial fission. At the same time, by up-regulating the level of the Mfn2, Celastrol also promoted mitochondrial fusion. In addition, we found that the nuclear factor-k-gene binding (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 signaling pathways aided the drug's anti-inflammatory effects. We also explored the relationship between Celastrol and the nuclear receptor Nur77 and found that it could up-regulate the expression of Nur77.ConclusionsOur study found that Celastrol could reduce inflammation by regulating Drp1 dependent mitochondrial fission and fusion, as well as the ERK1/2, p38, NF-κB signaling pathways. This finding provides a strong direction for the development of new anti-inflammatory drugs for atherosclerosis.

Project description:BackgroundType 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood.MethodsHere, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction.ResultsAs previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings.ConclusionsOverall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. Video Abstract.

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Rosiglitazone reduces diabetes angiopathy by inhibiting mitochondrial dysfunction dependent on regulating HSP22 expression.

Publications

Rosiglitazone reduces diabetes angiopathy by inhibiting mitochondrial dysfunction dependent on regulating HSP22 expression.

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