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Erythropoietin and AAA: Abdominal aortic aneurysm (AAA) is a common vascular disease, but its pathogenesis has not been fully elucidated. Here, Zhang and colleagues developed a murine model of AAA by administering high doses of erythropoietin, which led to aneurysm formation regardless of ApoE status or angiotensin II infusion, unlike the commonly used murine AAA model. Endothelial cells were critical to erythropoietin's effects on the aorta, and JAK2/STAT5 pathway activation was implicated in this process. The authors also found a correlation between erythropoietin concentrations and AAA in patients, suggesting that the link between erythropoietin and AAA deserves further investigation in humans. Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease, but the underlying mechanisms remain unknown. Here, we tested the hypothesis that erythropoietin (EPO) may promote the formation of AAA. We found that EPO dose-dependently promoted the formation of AAA in both Apoe−/− (66.7%) and wild-type (WT) (60%) mice receiving a high dose of EPO. EPO monoclonal antibodies given to Apoe−/− mice receiving angiotensin II (AngII) stimulation resulted in a markedly lower incidence of AAA (from 86.7 to 20%, P < 0.001), and EPO receptor (EPOR) knockdown in Epor+/−Apoe−/− mice substantially reduced the incidence of AAA compared to Apoe−/− mice after AngII stimulation (from 86.7 to 45.5%, P < 0.05), further supporting the finding that EPO is a contributor to AAA formation. EPO-induced AAA resulted in increased microvessels, phagocyte infiltration, and matrix metalloproteinase secretion, as well as reduced collagen and smooth muscle cells (SMCs). Experiments in vitro and ex vivo demonstrated that EPO induced proliferation, migration, and tube formation of endothelial cells via the JAK2/STAT5 signaling pathway. In humans, serum EPO concentrations were higher in patients with AAA than in healthy individuals and correlated with the size of the AAA, suggesting a potential link between EPO and the severity of AAA in humans. In conclusion, we found that EPO promotes the formation of AAA in both Apoe−/− and WT mice by enhancing angiogenesis, inflammation, collagen degradation, and apoptosis of SMCs and that EPO/EPOR signaling is essential for AngII-induced AAA. The association between EPO and AAA in humans warrants further study. [ABSTRACT FROM AUTHOR]

Endothelial cell senescence is one of the main risk factors contributing to vascular diseases. As increasing number of "epigenetic drugs" entering clinical trials, understanding the mechanism of epigenetic regulation in vascular aging has significant implications in finding targets to cure vascular diseases. However, the epigenetic regulation of endothelial senescence remains unclear. Based on the findings that increased protein level of histone H3 lysine 4 (H3K4) methyltransferase Smyd3 and elevated H3K4me3 modification happened in angiotensin II (Ang II)‐induced senescence in rat endothelial cells, we are curious about whether and how Smyd3 can regulate endothelial senescence. We found that an increase of Smyd3 alone promoted senescence‐associated phenotypes, while knockdown of Smyd3 blocked senescence in endothelial cells. Furthermore, Smyd3‐specific inhibitor reversed vascular senescence‐associated phenotypes at cellular level. Importantly, Ang II‐induced vascular senescence can be greatly alleviated in Smyd3 knockout (KO) mice and those treated with Smyd3 inhibitor. Mechanistically, Smyd3 directly bound to the promoter region of Cdkn1a (coding for p21), then caused its increased H3K4me3 level and elevated gene expression, and ultimately gave rise to senescence‐associated phenotypes. Intriguingly, Smyd3‐mediated p21 upregulated expression also exists in human tissues of vascular disease, indicating it is probably an evolutionarily conserved mechanism in regulating vascular senescence. Thus, Smyd3 can act as a novel factor regulating endothelial senescence through transcriptionally promoting p21 expression. Blocking the Smyd3‐p21 signaling axis may also have potential medical implications in treating diseases related to vascular aging. [ABSTRACT FROM AUTHOR]

Backgrounds and aims: Increased arterial stiffness may increase cardiovascular morbidity and mortality. Angiotensin II type 1 receptor blockers (ARBs) are potentially useful in controlling the central blood pressure and arterial stiffness in mild to moderate essential hypertension, while the effects of ARBs in aged patients with essential hypertension are not entirely investigated. Methods: The carotid-femoral arterial pulse wave velocity (PWV) was measured in aged patients with essential hypertension. Results: In a cross-sectional study, PWV value was significantly higher in these old patients with essential hypertension, compared to patients without essential hypertension. In correlation analysis, PWV was associated positively with age, hypertension duration, and carotid atherosclerosis. However, there was no relationship between PWV and gender in aged patients with essential hypertension. In a perspective study, 6–12 months administration of ARBs (losartan, 50 mg/day; telmisartan, 40 mg/day; valsartan 80 mg/day; irbesartan, 150 mg/day) remarkably reduced PWV in aged patients with essential hypertension. Regression analyses of multiple factors indicated that the effects of ARBs on arterial stiffness were not associated with the reduction of blood pressure. Conclusion: ARB treatment is a negative risk factor of arterial stiffness in aged patients with essential hypertension. [ABSTRACT FROM AUTHOR]

Smoking is the only modifiable risk factor that is associated with the development, expansion and rupture of abdominal aortic aneurysm (AAA). However, the causative link between cigarette smoke and AAA is unknown. Here we report a causative link between smoking and AAA in vivo. Acute infusion of angiotensin II (AngII) or nicotine, a major component of cigarette smoke, markedly increased the incidence of AAA in apolipoprotein E (apoE) knockout (Apoe?/?) mice and in mice deficient in both apoE and the AMP-activated kinase ?1 subunit (AMPK-?1) (Apoe?/?; Prkaa1?/? mice). In contrast, genetic deletion of AMPK-?2 (Apoe?/?; Prkaa2?/? mice) ablated nicotine- or AngII-triggered AAA in vivo. Mechanistically, we found that both nicotine and AngII activated AMPK-?2 in cultured vascular smooth muscle cells (VSMCs), resulting in the phosphorylation of activator protein 2? (AP-2?) and consequent matrix metallopeptidase 2 (MMP2) gene expression. We conclude that smoking (through nicotine) instigates AAA through AMPK-?2-mediated AP-2?-dependent MMP2 expression in VSMCs. [ABSTRACT FROM AUTHOR]

The ubiquitin-proteasome system has been implicated in oxidative stress-induced endothelial dysfunction in cardiovascular diseases. However, the mechanism by which oxidative stress alters the ubiquitin-proteasome system is poorly defined. The present study was conducted to determine whether oxidative modifications of PA700, a 26S proteasome regulatory subunit, contributes to angiotensin II (Ang II)-induced endothelial dysfunction. Exposure of human umbilical vein endothelial cells to low concentrations of Ang II, but not vehicle, for 6 hours significantly decreased the levels of tetrahydro-l-biopterin (BH4), an essential cofactor of endothelial NO synthase, which was accompanied by a decrease in GTP cyclohydrolase I, the rate-limiting enzyme for de novo BH4 synthesis. In addition, Ang II increased both tyrosine nitration of PA700 and the 26S proteasome activity, which were paralleled by increased coimmunoprecipitation of PA700 and the 20S proteasome. Genetic inhibition of NAD(P)H oxidase or administration of uric acid (a peroxynitrite scavenger) or N(G)-nitro-l-arginine methyl ester (nonselective NO synthase inhibitor) significantly attenuated Ang II-induced PA700 nitration, 26S proteasome activation, and reduction of GTP cyclohydrolase I and BH4. Finally, Ang II infusion in mice decreased the levels of both BH4 and GTP cyclohydrolase I and impaired endothelial-dependent relaxation in isolated aortas, and all of these effects were prevented by the administration of MG132, a potent inhibitor for 26S proteasome. We conclude that Ang II increases tyrosine nitration of PA700 resulting in accelerated GTP cyclohydrolase I degradation, BH4 deficiency, and consequent endothelial dysfunction in hypertension. [ABSTRACT FROM AUTHOR]