Exogenous spermine attenuates rat diabetic cardiomyopathy via suppressing ROS-p53 mediated downregulation of calcium-sensitive receptor

Wang, Yuehong; Chen, Junting; Li, Siwei; Zhang, Xinying; Guo, Zhibo; Hu, Jing; Shao, Xiaoting; Song, Ningyang; Zhao, Yajun; Li, Hongzhu; Yang, Guangdong; Xu, Chi; Wei, Can

doi:10.1016/j.redox.2020.101514

Cited by 46 publications

(42 citation statements)

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“…DM model was induced by intraperitoneal injection of 1% streptozotocin (STZ) solution with a dose of 60 mg/Kg. The STZ solution was prepared by dissolving STZ (Sigma-Aldrich) in 0.1 mM citric acid-citrate sodium buffer (pH 4.5) [ 26 ]. The citric acid-citrate sodium buffer without STZ was intraperitoneally injected into normal rats as control.…”

Section: Methodsmentioning

confidence: 99%

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

et al. 2021

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Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

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Section: Methodsmentioning

confidence: 99%

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

et al. 2021

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“…A total of 45 rats were randomly divided into three groups: i) Control (n=15), 0.1 M sterile citrate buffer (pH 4.5) was injected intraperitoneally as a control at the same volume as that in the model group; ii) T1D (n=15), a single intraperitoneal injection of STZ (60 mg/kg, dissolved in 0.1 M, pH 4.5 citric acid-citrate sodium buffer) was used to establish the T1D model. When the concentration of serum glucose was >16.7 mmol/l, the T1D model was considered to be established successfully ( 14 ); and iii) T1D + Sp (n=15), spermine solution (2.5 mg/kg/day, dissolved in normal saline) was injected intraperitoneally every day for 2 weeks before STZ injection, followed by an injection of spermine (2.5 mg/kg/day) every other day for 12 weeks. Rats in each group were euthanized at week 12 of modeling.…”

Section: Methodsmentioning

confidence: 99%

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Zhang

Chen

et al. 2021

Int J Mol Med

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diabetic nephropathy (dN) is the primary cause of end-stage renal disease, which is closely associated with dysfunction of the podocytes, the main component of the glomerular filtration membrane; however, the exact underlying mechanism is unknown. Polyamines, including spermine, spermidine and putrescine, have antioxidant and anti-aging properties that are involved in the progression of numerous diseases, but their role in dN has not yet been reported. The present study aimed to explore the role of polyamines in DN, particularly in podocyte injury, and to reveal the molecular mechanism underlying the protective effect of exogenous spermine. Streptozotocin intraperitoneal injection-induced type 1 diabetic (T1d) rat models and high glucose (HG)-stimulated podocyte injury models were established. It was found that in T1d rat kidneys and HG-induced podocytes, ornithine decarboxylase (a key enzyme for polyamine synthesis) was downregulated, while spermidine/spermine N1-acetyltransferase (a key enzyme for polyamines degradation) was upregulated, which suggested that reduction of the polyamine metabolic pool particularly decreased spermine content, is a major factor in dN progression. In addition, hyperglycemia can induce an increased rat kidney weight ratio, serum creatinine, urea, urinary albumin excretion and glomerular cell matrix levels, and promote mesangial thickening and loss or fusion of podocytes. The expression levels of podocyte marker proteins (nephrin, cd2-associated protein and podocin) and autophagy-related proteins [autophagy protein 5, microtube-associated proteins 1A/1B light chain 3 (Lc3)II/Lc3I, Beclin 1 and phosphorylated (p)-AMPK] were downregulated, while cleaved caspase-3, P62 and p-mTOR were increased. These changes could be improved by pretreatment with exogenous spermine or rapamycin (autophagic agonist). In conclusion, spermine may have the potential to prevent diabetic kidney injury in rats by promoting autophagy via regulating the AMPK/mTOR signaling pathway.

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“…Lipid-lowering treatments (422,423) and antihypertensives (424,428,452) enhanced myocardial autophagy in preclinical models of T1DM and T2DM through different molecular mechanims, such as calcium-mediated autophagosome-lysosome fusion and receptors modulation. Despite some conflicting results (453), the antioxidant supplements, resveratrol (327,432,433,454,455), spermidine (437)(438)(439)(440), and epigallocatechin gallate (EGCG) (441)(442)(443)(444) protected the heart in clinical and preclinical studies in both types of diabetes, also by regulating myocardial autophagy. While the systemic effects of these treatments are essential, the cardiac-specific regulation of autophagy is necessary for the maintenance of cardiac function in diabetes.…”

Section: Targeting Autophagymentioning

confidence: 99%

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Kaur

Raja

Ruiz-Velasco

et al. 2020

Front. Cardiovasc. Med.

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Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.

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Exogenous spermine attenuates rat diabetic cardiomyopathy via suppressing ROS-p53 mediated downregulation of calcium-sensitive receptor

Cited by 46 publications

References 46 publications

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

Exogenous spermine attenuates diabetic kidney injury in rats by inhibiting AMPK/mTOR signaling pathway

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

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