Recently, increasing evidences had suggested that long noncoding RNAs (LncRNAs) are involved in a wide range of physiological and pathophysiological processes. Here we determined the LncRNA expression profile using microarray technology in mouse livers after ischemia/reperfusion treatment. Seventy one LncRNAs were upregulated, and 27 LncRNAs were downregulated in ischemia/reperfusion-treated mouse livers. Eleven of the most significantly deregulated LncRNAs were further validated by quantitative PCR assays. Among the upregulated LncRNAs confirmed by quantitative PCR assays, AK139328 exhibited the highest expression level in normal mouse livers. siRNA-mediated knockdown of hepatic AK139328 decreased plasma aminotransferase activities, and reduced necrosis area in the livers with a decrease in caspase-3 activation after ischemia/reperfusion treatment. In ischemia/reperfusion liver, knockdown of AK139328 increased survival signaling proteins including phosphorylated Akt (pAkt), glycogen synthase kinase 3 (pGSK3) and endothelial nitric oxide synthase (peNOS). Furthermore, knockdown of AK139328 also reduced macrophage infitration and inhibited NF-κB activity and inflammatory cytokines expression. In conclusion, these findings revealed that deregulated LncRNAs are involved in liver ischemia/reperfusion injury. Silencing of AK139328 ameliorated ischemia/reperfusion injury in the liver with the activation of Akt signaling pathway and inhibition of NF-κB activity. LncRNA AK139328 might be a novel target for diagnosis and treatment of liver surgery or transplantation.

Endogenous CSE/H2S directly sulfhydrated SIRT1, enhanced SIRT1 binding to zinc ion, then promoted its deacetylation activity, and increased SIRT1 stability, thus reducing atherosclerotic plaque formation. Antioxid. Redox Signal. 00, 000-000.

No abstract

Catestatin (CST) is a catecholamine secretion inhibiting peptide as non-competitive inhibitor of nicotinic acetylcholine receptor. CST play a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. Cardiomyocytes endogenously produced CST and its expression was reduced after I/R. CST pretreatment decreased apoptosis especially endoplasmic reticulum (ER) stress response during I/R. The protection of CST was confirmed in H9c2 cardiomyoblasts under Anoxia/reoxygenation (A/R). In contrast, siRNA-mediated knockdown of CST exaggerated ER stress induced apoptosis. The protective effects of CST were blocked by extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor PD90895 and phosphoinositide 3-kinase (PI3 K) inhibitor wortmannin. CST also increased ERK1/2 and protein kinase B (Akt) phosphorylation and which was blocked by atropine and selective type 2 muscarinic acetylcholine (M2) receptor, but not type 1 muscarinic acetylcholine (M1) receptor antagonist. Receptor binding assay revealed that CST competitively bound to the M2 receptor with a 50% inhibitory concentration of 25.7 nM. Accordingly, CST inhibited cellular cAMP stimulated by isoproterenol or forskolin, and which was blocked by selective M2 receptor antagonist. Our findings revealed that CST binds to M2 receptor, then activates ERK1/2 and PI3 K/Akt pathway to inhibit ER stress-induced cell apoptosis resulting in attenuation cardiac I/R injury.

Background: Hydrogen sulfide (H 2 S) has anti-hypertension and anti-inflammatory effects, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4 + T cells. However, the role of CD4 + T-cell endogenous CSE/H 2 S in the development of hypertension is unclear. Methods: Peripheral blood lymphocytes were isolated from hypertensive patients or spontaneously hypertensive rats (SHRs), then H 2 S production and expression of its generation enzymes, cystathionine β synthase (CBS) and CSE, were measured to determine the major H 2 S generation system changes in hypertension. Mice with CSE-specific knockout in T cells (CKO, by CD4 cre mice hybridization) and CD4 null mice were generated for investigating the pathophysiological relevance of the CSE/H 2 S system. Results: In lymphocytes, H 2 S from CSE but not CBS responded to blood pressure (BP) changes, supported by lymphocyte CSE protein changes and negative correlation between H 2 S production with systolic BP (sBP) and diastolic BP (dBP) but positive correlation with serum level of interleukin 10 (IL-10, an anti-inflammatory cytokine). Deletion of CSE in T cells elevated BP (5-8 mmHg) under the physiological condition and exacerbated angiotensin II (AngII)-induced hypertension. In keeping with hypertension, mesenteric artery dilation impaired, association with arterial inflammation, an effect attributed to reduced immunoinhibitory T regulatory cell (Treg) numbers in blood and kidney, thus causing excess CD4 + and CD8 + T-cell infiltration in perivascular adipose tissues and kidney. CSE knockout CD4 + -T cell transfer into CD4 null mice, also showed the similar phenotypes confirming the role of endogenous CSE/H 2 S action. Adoptive transfer of Tregs (to CKO mice) reversed hypertension, vascular relaxation impairment and immunocyte infiltration, which confirmed that CKO-induced hypertension was due in part to the reduced Treg numbers. Mechanistically, endogenous CSE/H 2 S promoted Treg differentiation and proliferation by activating AMP-activated protein kinase (AMPK). In part, it depended on activation of its upstream kinase, liver kinase B1 (LKB1), by sulfhydration to facilitate its substrate binding and phosphorylation. Conclusions: The constitutive sulfhydration of LKB1 by CSE-derived H 2 S activates its target kinase, AMPK, and promotes Treg differentiation and proliferation, which attenuates the vascular and renal immune-inflammation, thereby preventing hypertension.