Drp-1 as Potential Therapeutic Target for Lipopolysaccharide-Induced Vascular Hyperpermeability

Abstract

Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.

Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson’s Disease Models

“…Next, we assessed Timm23 mRNA expression, which has been shown to attenuate MPTP-induced denervation at the level of dopaminergic cell bodies in the substantia nigra pars compacta [ 31 ]. As shown in an endothelial cell study published earlier [ 32 ], we found that LPS treatment downregulated the expression of mRNA encoding Timm23 ( Figure 4 B). Similar to HIF1α, ZNS ameliorated the expression of Timm23 mRNA ( Figure 4 D).…”

Differential Transcriptomic Profiles Following Stimulation with Lipopolysaccharide in Intestinal Organoids from Dogs with Inflammatory Bowel Disease and Intestinal Mast Cell Tumor

“…Mitochondrial protein, translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), promotes the proliferation and resistance to apoptosis and serves as a marker of mitophagy activity [ 122 ]. Reduced TOMM20 expression in response to LPS treatment implies that LPS activates mitophagy [ 123 ], resulting in decreased proliferation in the IBD colonoids (as observed in the current study). In the tumor cells, enhanced eIF3F expression inhibits translation, cell growth, and cell proliferation and induces apoptosis, whereas knockdown of eIF3f inhibits apoptosis, showing the role of eIF3f as an essential negative regulator of cell growth and proliferation [ 124 , 125 ].…”

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway

“…Mitophagy is the evolutionarily conserved process of repairing poorly structured mitochondria with the help of lysosomes [ 11 ]. Mitophagy has been reported to preserve microvascular structure and function under various pathophysiological conditions, including myocardial I/R injury [ 4 ], diabetes-related microvascular damage [ 12 ], sepsis-associated microcirculatory injury [ 13 ] and smoke-induced pulmonary endothelial injury [ 14 ]. However, it has been difficult to find an effective drug that specifically activates mitophagy and alleviates mitochondrial damage to improve the resistance of microvessels to I/R injury.…”