Overexpression of glyceraldehyde 3‐phosphate dehydrogenase prevents neurovascular degeneration after retinal injury

Zhang

et al. 2017

Sci Rep

Self Cite

In this study we quantified the alterations of retinal histone post-translational modifications (PTMs) in diabetic rats using a liquid chromatography - tandem mass spectrometry (LC-MS/MS) approach. Some diabetic rats were subsequently treated with minocycline, a tetracycline antibiotic, which has been shown to inhibit the diabetes-induced chronic inflammation in the retinas of rodents. We quantified 266 differentially modified histone peptides, including 48 out of 83 methylation marks with significantly different abundancein retinas of diabetic rats as compared to non-diabetic controls. About 67% of these marks had their relative abundance restored to non-diabetic levels after minocycline treatment. Mono- and di-methylation states of histone H4 lysine 20 (H4K20me1/me2), markers related to DNA damage response, were found to be up-regulated in the retinas of diabetic rats and restored to control levels upon minocycline treatment. DNA damage response biomarkers showed the same pattern once quantified by western blotting. Collectively, this study indicates that alteration of some histone methylation levels is associated with the development of diabetic retinopathy in rodents, and the beneficial effect of minocycline on the retinas of diabetic rodents is partially through its ability to normalize the altered histone methylation levels.

Section: Resultssupporting

confidence: 74%

Abnormal levels of histone methylation in the retinas of diabetic rats are reversed by minocycline treatment

Zhang

et al. 2017

Sci Rep

Self Cite

“…GAPDH is implicated in numerous cell functions; however, its role in cell death remains controversial and poorly understood (36). Whereas some reports indicate a proapoptotic function for GAPDH (37-39), others demonstrated a protective role (40)(41)(42)(43). The current paradigm considers GAPDH as a master switch in the regulation of cell death (44).…”

Section: Discussionmentioning

confidence: 99%

Nuclear complex of glyceraldehyde‐3‐phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant‐induced cell death

Hou¹,

Snarski²,

Higashi³

et al. 2017

FASEB j.

Atherosclerotic plaque destabilization is the major determinant of most acute coronary events. Smooth muscle cell (SMC) death contributes to plaque destabilization. Here, we describe a novel antiapoptotic mechanism in vascular SMCs that involves interaction of nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with apurinic/apyrimidinic endonuclease 1 (Ape1), the major oxidized DNA repair enzyme. GAPDH down-regulation potentiated HO-induced DNA damage and SMC apoptosis. Conversely, GAPDH overexpression decreased DNA damage and protected SMCs against apoptosis. Ape1 down-regulation reversed the resistance of GAPDH-overexpressing cells to DNA damage and apoptosis, which indicated that Ape1 is indispensable for GAPDH-dependent protective effects. GAPDH bound Ape1 in the SMC nucleus, and blocking (or oxidation) of GAPDH active site cysteines suppressed GAPDH/Ape1 interaction and potentiated apoptosis. GAPDH up-regulated Ape1 a transcription factor homeobox protein Hox-A5-dependent mechanism. GAPDH levels were reduced in atherosclerotic plaque SMCs, and this effect correlated with oxidative stress and SMC apoptosis. Thus, we demonstrated that nuclear GAPDH/Ape1 interaction preserved Ape1 activity, reduced DNA damage, and prevented SMC apoptosis. Suppression of SMC apoptosis by maintenance of nuclear GAPDH/Ape1 interactions may be a novel therapy to increase atherosclerotic plaque stability.-Hou, X., Snarski, P., Higashi, Y., Yoshida, T., Jurkevich, A., Delafontaine, P., Sukhanov, S. Nuclear complex of glyceraldehyde-3-phosphate dehydrogenase and DNA repair enzyme apurinic/apyrimidinic endonuclease I protect smooth muscle cells against oxidant-induced cell death.

“…For immunofluorescence staining, primary antibody against PDGFRα (AF1062, 1:200 dilution, R&D Systems) or Ki67 (sc15402, 1:100 dilution, Santa Cruz) was applied overnight. The sections were then incubated with anti‐goat or anti‐rabbit secondary antibody followed by DAPI staining, and images were taken . The number of cells with positive staining for both Ki67 and PDGFRα per field was determined.…”

Section: Methodsmentioning

confidence: 99%

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

et al. 2020

Self Cite

Repeated cycles of weight loss and regain, known as weight cycling, is often seen when people try to lose weight. The exact pathophysiological effects and the underlying mechanisms of weight cycling remain largely unclear. Here, we report that weight cycling induced by alternating feeding mice with a low‐fat diet or a high‐fat diet in a 1‐week switch protocol caused further increased epididymal white adipose tissue (eWAT) weight, preadipocyte proliferation, hepatic inflammation, fasting blood glucose level, and glucose intolerance, compared with the continuously HF‐fed mice. Combining the secretory protein database with RNA‐sequencing and quantitative PCR (qPCR) results in eWAT, the mRNA levels of several adipokines, including Retn (encoding resistin), were found altered by weight cycling. A transcriptional co‐factor Lmo4 was found regulated by weight cycling; Lmo4 enhanced preadipocyte proliferation, in vitro adipogenesis, transcription of Retn, and resistin secretion in 3T3‐L1 cells. Primary mouse hepatocytes administrated with recombinant mouse resistin (rm‐resistin), or exposed to media from Lmo4‐overexpressed 3T3‐L1 cells, showed increased inflammatory responses and gluconeogenesis. Furthermore, rm‐resistin‐injected normal chow‐fed mice showed upregulated blood glucose level by increasing gluconeogenesis, and upregulated the hepatic inflammatory responses. Together, our results suggest a regulatory role of Lmo4‐resistin signaling in weight cycling, indicating a crosstalk between the adipose tissue and liver.