Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2-mediated CyPA secretion and CD147-ERK1/2-cyclin pathway

Abstract

Reactive oxygen species-induced cyclophilin A (CyPA) release from vascular smooth muscle cells (VSMCs) may be inhibited by simvastatin in vitro. The present study aimed to further examine the effect of simvastatin on serum CyPA levels and the basigin (CD147)-extracellular signal-regulated kinase (ERK) 1/2-cyclin pathway during thoracic aorta remodeling. The mechanisms through which simvastatin may inhibit CyPA secretion from VSMCs were further investigated. Serum CyPA levels and the expression kinetics of CyPA-associated signaling pathways were examined following simvastatin treatment in rat thoracic aortas during hypertension. Cell lysates were prepared from middle layer of thoracic aortas at 1, 4, 8 and 12 weeks subsequent to surgery. ELISA analysis revealed that serum CyPA levels were gradually increased with the progression of thoracic aorta remodeling. Western blotting demonstrated that the expression of CD147, phosphorylated-ERK1/2, cyclin D1, cyclin A, and cyclin E were increased with the progression of thoracic aorta remodeling. Simvastatin administration for 4, 8 and 12 weeks diminished all these changes, as observed in the hypertensive group. VSMCs from simvastatin-treated rats secreted a decreased amount of CyPA compared with VSMCs from hypertensive rats. In addition, pretreatment with geranylgeraniol partly reversed the inhibitory effect of simvastatin on LY83583-induced CyPA secretion in cultured VSMCs, whereas GGTI-298 and KD025 [a selective Rho-associated protein kinase 2 (ROCK2) inhibitor] mimicked the inhibitory effect of simvastatin. The present study demonstrated that simvastatin alleviated thoracic aorta remodeling by reducing CyPA secretion and expression of the CD147-ERK1/2-cyclin signaling pathway. In addition, the results of the present study demonstrated that the Rho-ROCK2 pathway mediated CyPA secretion from VSMCs.

Tanshinone IIA Combined With Cyclosporine A Alleviates Lung Apoptosis Induced by Renal Ischemia-Reperfusion in Obese Rats

“…HE staining was performed as previously reported. After paraffin embedding, lung tissues were sectioned into 5-μm-thick sections ( 45 ). After immersion in paraformaldehyde (4%) for 24 h and then dehydration with ethanol (70%), we used H&E staining to stain the lung tissues and then visualized lung tissues with light microscopy.…”

“…We used the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay [ In Situ Cell Death Detection Kit (Roche, Germany)] to detect apoptosis. As described in the HE staining section ( 45 ), we used 5-μm-thick sections to perform TUNEL staining. After deparaffinization and rehydration, protease K (10 μg/ml) was added to the sections for 15 min.…”

Platelet surface expression of cyclophilin A is associated with increased mortality in patients with symptomatic coronary artery disease

“…Complex, yet fast mechanisms for the secretion of abundant intracellular CyPA have been described in several cell types. In vascular smooth muscle cells (VSMCs) actin remodeling and myosin II activation downstream of Rho‑ROCK2 signaling have been described to be a pathophysiologically relevant source of extracellular CyPA …”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…The Statin class of drugs, which upregulate eNOS, have neuroprotective properties in experimental animal models of stroke (Vaughan and Delanty, 1999). The upregulation of eNOS by Statins is mediated by inhibition of small GTPase RhoA (Sawada and Liao, 2009), reducing activation of RhoA's downstream effector ROCK2 (Hao et al, 2016;Tang F. C. et al, 2017). Using pharmacological intervention to directly target eNOS function might represent an interesting avenue to promote stroke recovery.…”