Angiotensin II (Ang II) is the predominant effector peptide of the renin–angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II–induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II–induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77 −/− mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77 −/− mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22α and α-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II–induced β-catenin signaling pathway activation by promoting β-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II–induced VSMC proliferation, migration, and phenotypic switching via the downregulation of β-catenin activity. Nur77 may reduce Ang II–induced vascular remodeling involved in many cardiovascular diseases.
Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.
Background: The aim of this study was to assess the preventive effect of xuezhikang (XZK) to replace atorvastatin on the contrast media-induced acute kidney injury (CI-AKI). Methods: The male Sprague-Dawley rats were divided into five groups: group 1 (sham), injected with normal saline; group 2 (XZK), treated with XZK; group 3 contrast media (CM), injected with CM; group 4 (CM þ ATO), injected with CM þ pretreatment with atorvastatin; group 5 (CM þ XZK), injected with CM þ pretreatment with XZK. Twenty-four hours after injection with normal saline or CM, the blood sample and the kidneys were collected for the measurement of biochemical parameters, oxidative stress markers, nitric oxide production, inflammatory parameters, as well as renal histopathology and apoptosis detection. Results: Our results indicated that XZK restored the renal function by reducing serum blood urea nitrogen (BUN) and serum creatinine (Scr), depressing renal malondialdehyde (MDA), increasing renal NO production, decreasing TNF-A and IL-6 expression, attenuating renal pathological changes and inhibiting the apoptosis of renal tubular cells. Conclusion: XZK's therapeutic effect is similar, or even better than atorvastatin at the same effectual dose in some parts.
BackgroundContrast‐induced acute kidney injury (CI‐AKI) was traditionally defined as an increase in serum creatinine (sCr) after contrast media exposure. Recently, serum cystatin C (sCyC) has been proposed as an alternative to detect acute changes in renal function. The clinical implications of combining sCyC and sCr to diagnose CI‐AKI remain unknown.Methods and ResultsOne thousand seventy‐one consecutive patients undergoing coronary angiography/intervention were prospectively enrolled. SCyC and sCr were assessed at baseline and 24 to 48 hours after contrast media exposure. CI‐AKI determined by sCr (CI‐AKI sCr) was defined as an sCr increase greater than 0.3 mg/dL or 50% from baseline. Major adverse events at 12 months were assessed. CI‐AKI sCr developed in 25 patients (2.3%). Twelve‐month follow‐up was available for 1063 patients; major adverse events occurred in 61 patients (5.7%). By receiver operating characteristic curve analysis, an sCyC increase of greater than 15% was the optimal cutoff for CI‐AKI sCr detection, which occurred in 187 patients (17.4%). To evaluate the use of both sCyC and sCr as CI‐AKI diagnostic criteria, we stratified patients into 3 groups: no CI‐AKI, CI‐AKI detected by a single marker, and CI‐AKI detected by both markers. Multivariable logistic regression revealed that the predictability of major adverse events increased in a stepwise fashion in the 3 groups (no‐CI‐AKI group as the reference, CI‐AKI detected by a single marker: odds ratio=2.25, 95% CI: 1.24–4.10, P<0.01; CI‐AKI detected by both markers: odds ratio=10.00, 95% CI: 3.13–31.91, P<0.001).ConclusionsCombining sCyC and sCr to diagnose CI‐AKI would be beneficial for risk stratification and prognosis in patients after contrast media exposure.
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