Calpain-1 resident in lipid raft/caveolin-1 membrane microdomains plays a protective role in endothelial cells

Liao

et al. 2018

Front. Cell. Neurosci.

The purpose of the current study was to investigate whether peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) can interact with calpastatin (CAST) and regulate CAST/calpain2, under excessive glutamate conditions, and subsequently regulate necrosis in rat retinal neurons. Glutamate triggered CAST/calpain2-mediated necrosis regulation in primary cultured retinal neurons, as demonstrated by propidium iodide-staining and lactate dehydrogenase assay. Co-IP results and a computer simulation suggested that Pin1 could bind to CAST. Western blot, real-time quantitative polymerase chain reaction, immunofluorescence, and phosphorylation analysis results demonstrated that CAST was regulated by Pin1, as proven by the application of juglone (i.e., a Pin1 specific inhibitor). The retinal ganglion cell 5 cell line, combined with siRNA approach and flow cytometry, was then used to verify the regulatory pathway of Pin1 in CAST/calpain2-modulated neuronal necrosis that was induced by glutamate. Finally, in vivo studies further confirmed the role of Pin1 in CAST/calpain2-modulated necrosis following glutamate excitation, in the rat retinal ganglion cell and inner nuclear layers. In addition, a flash electroretinogram study provided evidence for the recovery of impaired visual function, which was induced by glutamate, with juglone treatment. Our work aims to investigate the involvement of the Pin1-CAST/calpain2 pathway in glutamate-mediated excitotoxicity.

Section: Discussionsupporting

confidence: 59%

Pin1 Promotes Regulated Necrosis Induced by Glutamate in Rat Retinal Neurons via CAST/Calpain2 Pathway

Liao

et al. 2018

Front. Cell. Neurosci.

“…Calmodulin interacts with eNOS to activate eNOS. HSP90 increases eNOS activity by promoting the dissociation of eNOS from caveolin‐1 or directly changing the conformation of eNOS 10‐12 …”

Section: Introductionmentioning

confidence: 99%

“…HSP90 increases eNOS activity by promoting the dissociation of eNOS from caveolin-1 or directly changing the conformation of eNOS. [10][11][12] Epimedium is a traditional Chinese medicine for treatment of ED. 13 Although icariin cannot reverse the apoptosis and fibrosis which has occurred in penile cavernous tissue in SHR, it has been found to improve erectile function by activating phosphorylation of eNOS (Ser-1177) through PI3K/ Akt/eNOS signaling pathway and inhibiting the RhoA/ Rho kinase signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Icariin modulates eNOS activity via effect on post‐translational protein‐protein interactions to improve erectile function of spontaneously hypertensive rats

et al. 2020

Background Type 5 phosphodiesterase inhibitor (PDE5I) has become the first‐line treatment for erectile dysfunction (ED). However, its effective rate for hypertension ED is only 60%‐70%. How to improve the efficacy of ED treatment is the focus of current research. Objective To explore whether icariin can improve the erectile function of spontaneously hypertensive rats (SHR) by affecting post‐translational protein‐protein interactions to regulate endothelial nitric oxide synthetase (eNOS) activity. Method Twelve‐week‐old healthy male SHR rats and Wistar‐Kyoto rats (WKY) were randomly divided into four groups: SHR control group, SHR + icariin (10 mg/kg·d gavage) treatment group, WKY control group, and WKY + icariin (10 mg/kg·d gavage) treatment group (n = 5). After 4 weeks, the maximum penile intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of heat‐shock protein 90 (Hsp90), caveolin‐1, calmodulin, p‐eNOS, and eNOS in penile cavernous tissue and the content of nitric oxide (NO) and cGMP were measured. The interaction between eNOS and Hsp90, caveolin‐1, and calmodulin were detected by immunoprecipitation. Result The ICPmax/MAP in the SHR + icariin treatment group (0.08 ± 0.01, 0.23 ± 0.07, 0.40 ± 0.05) was significantly higher than the SHR group (0.03 ± 0.01, 0.13 ± 0.03, 0.21 ± 0.02) under 3V and 5V electrical stimulations (P < .05). Compared with the SHR group, the expression of HSP90, calmodulin, P‐eNOS, eNOS, and P‐eNOS/eNOS in the penile cavernous tissue of rats in the WKY group and the SHR + icariin treatment group were significantly increased (P < .05), and the expression of caveolin‐1 was significantly decreased (P < .05). The NO content (2.16 ± 0.22 μmol/g) and cGMP concentration (3.69 ± 0.12 pmol/mg) in the SHR + icariin treatment group were significantly higher than those in the SHR group (1.01 ± 0.14 μmol/g, 2.31 ± 0.22 pmol/mg) (P < .05). Compared with the SHR group, the interaction between eNOS and HSP90 in the cavernosa of the rats in the SHR + icariin treatment group was significantly increased (P < .05), the interaction between eNOS and caveolin‐1 was significantly decreased (P < .01), and the interaction between eNOS and calmodulin did not significantly change. Discussion and Conclusion Up‐regulating the expression of HSP90 and calmodulin and inhibiting caveolin‐1 in SHR corpus cavernosum, promoting the interaction between eNOS and HSP90, inhibiting the interaction between eNOS and caveolin‐1, increasing p‐eNOS/eNOS, may be the mechanism of icariin that improves SHR erectile function.

“…It is reported that Calpain-1 is a defensive mechanism in neuronal cell activation through employing selective inhibitors. Insertion and activation of Calpain-2 on the plasma membrane are responsible for cell damage (Martines et al 2017 ). Studies have previously shown that viral ORFs generate proteins that activate the cellular death mechanism.…”

Section: Putative Calpain Inhibitorsmentioning

confidence: 99%

The key role of Calpain in COVID-19 as a therapeutic strategy

2022

COVID-19 is one of the viral diseases that has caused many deaths and financial losses to humans. Using the available information, this virus appears to activate the host cell-death mechanism through Calpain activation. Calpain inhibition can stop its downstream cascade reactions that cause cell death. Given the main roles of Calpain in the entry and pathogenicity of the SARS-CoV-2, its inhibition can be effective in controlling the COVID-19. This review describes how the virus activates Calpain by altering calcium flow. When Calpain was activated, the virus can enter the target cell. Subsequently, many complications of the disease, such as inflammation, cytokine storm and pulmonary fibrosis, are caused by virus-activated Calpain function. Calpain inhibitors appear to be a potential drug to control the disease and prevent death from COVID-19.