New Insights of µ-Calpain in the Pathogenesis of Diabetic Vascular Injury

Zhang, Yingmei; Ren, Jun

doi:10.2337/db14-1502

Cited by 8 publications

(4 citation statements)

References 20 publications

(29 reference statements)

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“…Hcyis an important intermediate in one-carbon metabolism that involves the conversion of methionine to cysteine, and folate interconversions. Deficiencies in these pathways lead to the accumulation of Hcy and its metabolites in the blood, which causes endothelial dysfunction (endothelial cell injury and autophagy) [20-22]. …”

Section: Discussionmentioning

confidence: 99%

Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells

Zhang

Zhang²,

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Genetic or nutritional deficiencies in homocysteine (Hcy)metabolism lead to the accumulation of Hcy and its metabolites in the blood. This can lead to hyperhomocysteinemia (HHcy), which is an independent risk factor for cardiovascular disease. Studies have shown that HHcy leads to endothelial dysfunction, a hallmark of atherosclerosis, which may explain this link. The precise mechanism remains unclear, but a strong possibility is excessive HHCy-induced autophagy. Autophagy has been better studied in ischemia/reperfusion (I/R) injuries, and previous work showed that Oxymatrine (OMT), a quinolizidine alkaloid, protects cells against myocardial I/R injury by inhibiting autophagy. The aim of this study was to determine whether OMT inhibits autophagy in HHcy. Methods: Autophagy in HUVEC cells treated with Hcy in the presence and absence of OMT was visualized bytransmission electron microscopy and the degree was determined by western blotting and qRT-PCR. Small interfering RNA (siRNA)was used to determine the efficiency of Macrophage migration inhibitory factor (MIF) inhibition. Cell apoptosis wasdetected by western blotting and flow cytometric analysis. Results: OMT inhibited autophagy, MIF, and mTOR in HUVECs during Hcy exposure, depending on the dose. siRNA-mediated MIF knockdown decreased Hcy-induced autophagy, while administration of 3-methyladenosine and rapamycin showed that they also induce autophagy. Furthermore, OMT dose-dependently inhibited the Hcy-induced HUVEC apoptosis/death. Conclusions: These results suggest that Hcy can evokeautophagy-activated HUVEC apoptosis/death via a MIF/mTOR signaling pathway, which can be reversed by OMT. Our results provide a new insight into a functional role of OMT in the prevention of Hcy-induced HUVEC injury and death.

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Section: Discussionmentioning

confidence: 99%

Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells

Zhang

Zhang²,

Tang

et al. 2018

Cell Physiol Biochem

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“…Calpain is a Ca 2+ -dependent protease, and the calpain superfamily possesses 15 genes in the human genome 13 . Several studies have revealed that over-activated calpain increases persistent Na + current via cleaving the Na + channel, stimulates protein kinase C, and destroys skeleton membrane proteins, α-fodrin and ankyrin-B, resulting in abnormal cell function 10,[14][15][16][17] . μ-calpain, a heterodimer consisting of a large catalytic subunit calpain-1 (CAPN1) and a small regulatory subunit, is present in the heart.…”

Section: Introductionmentioning

confidence: 99%

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts

Feng

Tang

et al. 2020

Cell Death Dis

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Previous studies indicated that Ca 2+ /calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca 2+-regulated protease μ-calpain to promote myocardial ischemia/ reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca 2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca 2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca 2+ flux using ryanodine and thapsigargin failed to prevent Ca 2+ paradox-induced heart injury. In contrast, the Ca 2+ paradox increased CaMKII auto-phosphorylation at Thr 287 , while the CaMKII inhibitor KN-62 and the Na + /Ca 2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca 2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/ reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

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“…The incidence rate of diabetes, a chronic disease characterized by increased glucose concentration in the blood, is increasing at an alarming rate ( Zhang and Ren, 2015 ). The diabetic population is mainly affected by vascular diseases involving multiple organ systems.…”

Section: Treatment Of Diabetesmentioning

confidence: 99%

Advances in pharmacological effects and mechanism of action of cinnamaldehyde

Guo,

Yan,

Jiang

et al. 2024

Front. Pharmacol.

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Cinnamaldehyde is extracted from Cinnamomum cassia and other species, providing diverse sources for varying chemical properties and therapeutic effects. Besides natural extraction, synthetic production and biotechnological methods like microbial fermentation offer scalable and sustainable alternatives. Cinnamaldehyd demonstrates a broad pharmacological range, impacting various diseases through detailed mechanisms. This review aims to encapsulate the diverse therapeutic effects of cinnamaldehyde, its molecular interactions, and its potential in clinical applications. Drawing on recent scientific studies and databases like Web of Science, PubMed, and ScienceDirect, this review outlines cinnamaldehyde’s efficacy in treating inflammatory conditions, bacterial infections, cancer, diabetes, and cardiovascular and kidney diseases. It primarily operates by inhibiting the NF-κB pathway and modulating pro-inflammatory mediators, alongside disrupting bacterial cells and inducing apoptosis in cancer cells. The compound enhances metabolic health by improving glucose uptake and insulin sensitivity and offers cardiovascular protection through its anti-inflammatory and lipid-lowering effects. Additionally, it promotes autophagy in kidney disease management. Preclinical and clinical research supports its therapeutic potential, underscoring the need for further investigation into its mechanisms and safety to develop new drugs based on cinnamaldehyde.

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New Insights of µ-Calpain in the Pathogenesis of Diabetic Vascular Injury

Cited by 8 publications

References 20 publications

Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells

Oxymatrine Inhibits Homocysteine-Mediated Autophagy via MIF/mTOR Signaling in Human Umbilical Vein Endothelial Cells

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts

Advances in pharmacological effects and mechanism of action of cinnamaldehyde

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