High Serum MiR-130a Levels Are Associated with Severe Perihematomal Edema and Predict Adverse Outcome in Acute ICH

Abstract

The development and/or progression of perihematomal edema (PHE) in patients with acute spontaneous intracerebral hemorrhage (ICH) vary substantially with different individuals. Although hematoma volume is a useful indicator for predicting PHE, its predictive power was not good at the early stage of ICH. Better predictors are urgently needed. In this study, we found that miR-130a was elevated in the serum of ICH patients and was an independent indicator positively associated with PHE volume within the first 3 days after onset. The R (2) was further evaluated when it is used in combination with hematoma mass. Serum miR-130a levels were associated with clinical outcome (National Institute of Health Stroke Scale (NIHSS) scores at day 14 and modified Rankin Scale (mRS) scores at day 90) only in patients with deep hematoma. Moreover, miR-130a was significantly increased in rat serum and perihematomal tissues and was in line with the change in brain edema. MiR-130a inhibitors reduced brain edema, blood-brain barrier (BBB) permeability, and increased neurological deficit scores, and miR-130a mimics increased monolayer permeability. Thrombin-stimulated brain microvascular endothelial cells (BMECs) were a main source of miR-130a under ICH. In the experimental model, the elevated miR-130a level was accompanied by the decreased caveolin-1 and increased matrix metalloproleinase (MMP)-2/9. Meanwhile, caveolin-1 (cav-1) was reduced by miR-130a mimics, accompanied by an increase in MMP-2/9 expression. The upregulated MMP-2/9 was then downregulated by cavtratin, a cav-1 scaffolding domain peptide. This regulation mechanism was authenticated in a thrombin-induced cellular ICH model. Our results suggest that serum miR-130a may serve as a useful early biomarker for monitoring post-ICH PHE and predicting prognosis and may be helpful in the decision-making of individualized therapy.

MicroRNA‐130a regulates cerebral ischemia–induced blood–brain barrier permeability by targeting Homeobox A5

“…RNA extraction and real‐time quantitative PCR (qPCR) were performed to evaluate the expression of miRNAs as previously reported (14). Total miRNAs from brain tissue, microvessels, or cells (BMEC, astrocytes, and pericytes) were extracted by using mirVana PARISTM RNA isolation kit according to the manufacturer's protocol.…”

Non-coding RNAs and neuroprotection after acute CNS injuries

“…Increased levels of circulating miRNAs like miR-522, miR-122, and miR-29c were observed in the plasma of ICH patients with hematoma compared to ICH patients without hematoma (Zheng et al, 2012). Blood miRNA profiling also indicated the possibility of identifying perihematoma edema (PHE) after ICH in both humans and rats (Zhu et al, 2015; Wang et al, 2016a). A correlation was observed between miR-126 levels in blood and the PHE volume in ICH patients (Zhu et al, 2015).…”

“…A correlation was observed between miR-126 levels in blood and the PHE volume in ICH patients (Zhu et al, 2015). The rat model of ICH indicated that increased levels of miR-29c and miR-122 in plasma correlates with PHE formation (Wang et al, 2016a). Rupture of intracranial aneurysms (IAs) is a major cause of hemorrhagic stroke, especially SAH (Krings et al, 2011).…”

Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease

“…Cavtratin decreases eNOS activity by mimicking the CAV1 inhibitory clamp (Figure 2B) and does not affect the function of other NOSs in vivo and targets eNOS to a significant extent 53 . Cavtratin reduces microvascular hyperpermeability and blocks tumor progression 52, 54 , restores tight junctions in C-C motif chemokine 2 (CCL2) treated brain microvascular endothelial cells (BMECs) 55 , inhibits matrix metalloproteinase-2/9 (MMP2/9) and cyclooxygenase-2 (COX2), which could lead to stabilization of atherosclerotic plaques and protective effects for intracerebral hemorrhages 56, 57 . Cavtratin also diminishes glia cell growth 58 and protects the blood-brain-barrier (BBB), when treated with vascular endothelial growth factor A (VEGF-A) in a mouse model of multiple sclerosis (MS) 59 .…”