Crocin Improves Endothelial Mitochondrial Dysfunction via GPx1/ROS/KCa3.1 Signal Axis in Diabetes

Abstract

Mitochondrial dysfunction contributes to excessive reactive oxygen species (ROS) generation, which is a dramatic cause to promote endothelial dysfunction in diabetes. It was previously demonstrated that crocin protected the endothelium based on its diverse medicinal properties, but its effect on the mitochondrion and the potential mechanism are not fully understood. In this study, mitochondrial function was analyzed during the process of excessive ROS generation in high glucose (HG)-cultured human umbilical vein endothelial cells (HUVECs). The role played by KCa3.1 was further investigated by the inhibition and/or gene silence of KCa3.1 in this process. In addition, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase 2 (NOX2), superoxide dismutase 1 (SOD1), and glutathione peroxidase 1 (GPx1) were also detected in this study. Our data showed that crocin improved mitochondrial dysfunction and maintained normal mitochondrial morphology by enhancing the mitochondrial membrane potential (MMP), mitochondrial mass, and mitochondrial fusion. Furthermore, KCa3.1 was confirmed to be located in the mitochondrion, and the blockade and/or silencing of KCa3.1 improved mitochondrial dysfunction and reduced excessive ROS generation but did not affect NOX2 and/or the SOD1 system. Intriguingly, it was confirmed that KCa3.1 expression was elevated by ROS overproduction in the endothelium under HG and/or diabetes conditions, while crocin significantly suppressed this elevation by promoting GPx1 and subsequently eliminating ROS generation. In addition, crocin enhanced CD31, thrombomodulin (TM), and p-/t-endothelial nitric oxide synthase (eNOS) expressions as well as NO generation and decreased vascular tone. Hence, crocin improved mitochondrial dysfunction through inhibiting ROS-induced KCa3.1 overexpression in the endothelium, which in turn reduced more ROS generation and final endothelial dysfunction in diabetes.

Citronellal Attenuates Oxidative Stress–Induced Mitochondrial Damage through TRPM2/NHE1 Pathway and Effectively Inhibits Endothelial Dysfunction in Type 2 Diabetes Mellitus

“…Moreover, CT was not only able to improve the decrease in mitochondrial membrane potential but also to inhibit the expression of NOX2, NOX4 and DRP1, thus alleviating the damage of mitochondria and endothelial cells caused by oxidative stress. These results were in accordance with previous studies [ 49 , 50 , 51 , 52 ].…”

An In Vitro Study of Saffron Carotenoids: The Effect of Crocin Extracts and Dimethylcrocetin on Cancer Cell Lines

“…In TE671 cells GSTM1 and SOD1 expression was abrogated in the presence of CRCs and DMCRT, respectively, at 72 h of exposure. Saffron’s phytochemicals at 72 h of exposure mitigated cell’s ability to maintain oxidative equilibrium and defend against oxidative stress, thus initiating cascades of apoptosis [ 205 , 206 , 207 , 208 ].…”

Crocins for Ischemic Stroke: A Review of Current Evidence

“…For example, CR inhibited hypoxia-inducible factor-1α which is an important molecular target in IS (Oruc et al, 2016) (Table 2). The action of CR on mitochondrial apoptosis is also important for their neuroprotective effects against IS (Li et al, 2021;Yousefsani et al, 2021), including casp 3, casp 8, casp 9, B-cell lymphoma-2 (Bcl-2), and Bcl-2 Associated X-protein (Bax) (Table 2). The key ROS-related enzymes targeted by CR and associated compounds or analogues include SOD, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and GPx Chen et al, 2015;Zhang et al, 2017b).…”