RESUMO
Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.
RESUMO
BACKGROUND: Geriatric hip fracture patients often present malnutrition during admission, which leads to higher morbidity and mortality. Protein-based oral nutrition supplements may improve nutritional status. We conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) according to the PRISMA guidelines to elucidate whether preoperative nutrition supplements can improve postoperative outcomes in geriatric hip fracture patients. METHODS: Only RCTs conducted to compare postoperative outcomes between geriatric hip fracture patients (>60âyears old) receiving preoperative oral protein-based nutrition supplement (ONS group) and those who receiving regular diet (Control group) were included. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception until August, 2021. Postoperative outcomes, including complications, length of hospital stay, and in-hospital mortality, were assessed. RESULTS: A total of 5 RCTs with 654 geriatric hip fracture patients (ONS group: 320 subjects; Control group 334 subjects) were included. Our data revealed that postoperative complications risk in the ONS group was significantly lower than in the Control group (odd's ratio: 0.48, 95% confidence intervals [CI]: 0.26-0.89, Pâ=â.02, I2â=â64%). However, no significant differences in the length of hospital stay (standardized mean difference: -0.35âdays, 95% CI: -1.68 to 0.98âdays, Pâ=â.61, I2â=â0%) and the risk of having postoperative in-hospital mortality (odd's ratio: 1.07, 95% CI: 0.43-2.63, Pâ=â.89, I2â=â54%) between these 2 groups were observed. Quality assessment revealed high risk of bias and significant data heterogeneity (I2>50%) in most included RCTs. CONCLUSION: Preoperative protein-based oral nutrition supplements exert beneficial, but limited, effects on postoperative outcomes in geriatric patients with hip fracture undergoing surgery.
