Phosphoproteomics analysis of diabetic cardiomyopathy in aging‐accelerated mice and effects of D‐pinitol

Abstract

Purpose:The molecular mechanisms of diabetic cardiomyopathy (DCM) development and D-pinitol (DP) in its treatment remain unclear. The present study is to explore the underlying mechanism of DCM in an elderly diabetic mouse model and to seek the protective targets of DP by phosphoproteomics. Experimental design:We used streptozotocin to induce diabetes in SAMP8 and DP (150 mg/kg/day) intragastrically administrated to diabetic mice for 8 weeks. The heart tissues were harvested for label-free phosphoproteomic analysis from diabetic mice. Some differentially regulated phosphorylation sites were confirmed by parallel reaction monitoring.Results: Our results showed that 612 phosphorylation sites on 454 proteins had their phosphorylation levels significantly changed in the heart of untreated diabetic mice (DM). Of these phosphorylation sites, 216 phosphorylation sites on 182 proteins were normalized after DP treatment. We analyzed the functional signaling pathways in the heart of DP treated diabetic mice (DMT), including glucagon signaling pathway, insulin signaling pathway, mitophagy, apoptosis, and longevity regulating pathway. Two consensus motifs identified were targeted by Src and epidermal growth factor receptor between DMT and DM groups. Conclusions and clinical relevance:Our study might help to better understand the mechanism of DCM, provide novel targets for estimating the protective effects of DP.

The regulation of MFG‐E8 on the mitophagy in diabetic sarcopenia via the HSPA1L‐Parkin pathway and the effect of D‐pinitol

“…This, in turn, helps alleviate DCM. 32 Our research findings suggest that the deficiency of mitophagy is reduced by DP via MFG‐E8 regulation, which contributes to alleviating symptoms of diabetic sarcopenia.…”

D‐pinitol alleviates diabetic cardiomyopathy by inhibiting the optineurin‐mediated endoplasmic reticulum stress and glycophagy signaling pathway

“…ERS plays a crucial role in the development of myocardial apoptosis and fibrosis in DCM. Endoplasmic reticulum is a complex intracellular membrane network, which regulates protein folding and modification (Li, Yu, et al, 2022; Li, Zhang, et al, 2022). A variety of factors including hyperglycemia, AGEs accumulation, oxidative stress, and ischemia, cause the accumulation of unfolded proteins, and trigger unfolded protein response, which ultimately leads to myocardial apoptosis and hypertrophy (Fernández et al, 2015; He et al, 2018).…”

“…Our previous research found that D‐pinitol (methyl ether of D‐chiro‐inositol, DP) could inhibit the myocardial apoptosis and fibrosis in STZ‐induced senescence‐accelerated prone 8 (SAMP8) mice. The protective effect of DP on DCM was related to the regulation of OPTN (Li et al, 2021; Li, Yu, et al, 2022; Li, Zhang, et al, 2022). DP is found in large quantities in soybean, carob pods, and legume foods.…”

“…The protective effect of DP on DCM was related to the regulation of OPTN (Li et al, 2021;Li, Yu, et al, 2022;Li, Zhang, et al, 2022). DP is found in large quantities in soybean, carob pods, and legume foods.…”

“…modification (Li, Yu, et al, 2022;Li, Zhang, et al, 2022). A variety of factors including hyperglycemia, AGEs accumulation, oxidative stress, and ischemia, cause the accumulation of unfolded proteins, and trigger unfolded protein response, which ultimately leads to myocardial apoptosis and hypertrophy (Fernández et al, 2015;He et al, 2018).…”