Ginsenoside Rb1 attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the JNK and p38 signaling pathways.

Abdominal aortic aneurysm (AAA), a life-threatening vascular disease, accounts for approximately 10% of the morbidity in people over 65 years old. No satisfactory approach is available to treat AAA. Ginsenosides Rb1 and Rg1 are primary ingredients of Panax notoginseng for the treatment of cardiovascular diseases, but their impact on AAA is unknown. An AAA model was established using an Ang II infusion in ApoE(-/-) mice. After continuous stimulation of Ang II for 28 days, suprarenal aortic aneurysms developed in 77% mice and 12% mice died suddenly due to AAA rupture. Administration of ginsenoside Rb1 (20 mg/kg/day), but not ginsenoside Rg1, significantly reduced the incidence and mortality of AAA. Ginsenoside Rb1 treatment dramatically suppressed Ang II-induced diameter enlargement, extracellular matrix degradation, matrix metalloproteinase (MMP) production, inflammatory cell infiltration, and vascular smooth muscle cell (VSMC) dysfunction. Mechanistic studies indicated that the protective effects of ginsenoside Rb1 were associated with the inactivation of JNK and p38 MAPK signaling pathways. A specific activator of JNK and p38, anisomycin, nearly abolished ginsenoside Rb1-driven suppression of MMP secretion by VSMCs. Ginsenoside Rb1, as a potential anti-AAA agent, suppressed AAA through inhibiting the JNK and p38 signaling pathways.

Zhang XJ ，He C ，Tian K ，Li P ，Su H ，Wan JB ... -  《-》

Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway.

Tsai SH ，Huang PH ，Peng YJ ，Chang WC ，Tsai HY ，Leu HB ，Chen JW ，Lin SJ ... -  《-》

Fucoidan attenuates angiotensin II-induced abdominal aortic aneurysms through the inhibition of c-Jun N-terminal kinase and nuclear factor κB activation.

Rupture of abdominal aortic aneurysm (AAA) is one of the leading causes of sudden death among the elderly. Most incidental AAAs are below the threshold for intervention at the time of detection; however, there is no evidence that commonly used cardiovascular drugs have clinical beneficial effects on AAA progression. Therefore, in addition to current cardiovascular risk-reducing treatments, an adjunctive medical therapy targeting the regulation of extracellular matrix metabolism is still required in the clinical setting. Fucoidan is an extract of brown seaweed and a sulfated polysaccharide. Emerging evidence suggests that fucoidan has potential cardiovascular applications. Numerous investigations of fucoidan in diseases of the cardiovascular system have mainly focused on its pleiotropic anti-inflammatory effects. Specifically, fucoidan has been shown to have matrix metalloproteinase (MMP)-reducing effects in several studies. We aimed to evaluate the beneficial effect of fucoidan on aneurysmal growth in a murine model of aortic aneurysm and further provide a rationale for using fucoidan as a medical adjunctive therapy. A murine model of angiotensin II (Ang II)-induced AAA was used to assess the therapeutic effects of fucoidan on AAA growth in vivo. The characteristics and quantification of AAAs were determined in situ. Human umbilical vein endothelial cells were used for studying the involved pathways in vitro. Western blotting was used to detect the involved signaling pathways both in vivo and in vitro. Treatment with fucoidan significantly reduced the incidence of AAA formation. Administration of fucoidan significantly attenuated Ang II-induced aortic expansion from 1.56 ± 0.76 mm to 1.09 ± 0.30 mm. Administration of fucoidan significantly suppressed MMP-2 and MMP-9 activities and reduced the grade of elastin degradation in vivo. In vitro, we found that fucoidan could ameliorate the Ang II-induced phosphorylation of c-Jun N-terminal kinase and nuclear factor κB p65, and it further reduced MMP and reactive oxygen species production. Fucoidan inhibits the progression of experimental AAA growth through the attenuation of proinflammatory nuclear factor κB and c-Jun N-terminal kinase activation. Fucoidan could be a potential medical adjunctive therapy for small AAAs.

Tsai SH ，Wang JC ，Liao WI ，Hsu YJ ，Lin CY ，Liao MT ，Huang PH ，Lin SJ ... -  《-》

Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways.

Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33-/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33-/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33-/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33-/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.

Nakao T ，Horie T ，Baba O ，Nishiga M ，Nishino T ，Izuhara M ，Kuwabara Y ，Nishi H ，Usami S ，Nakazeki F ，Ide Y ，Koyama S ，Kimura M ，Sowa N ，Ohno S ，Aoki H ，Hasegawa K ，Sakamoto K ，Minatoya K ，Kimura T ，Ono K ... -  《-》

Resveratrol Inhibits Growth of Experimental Abdominal Aortic Aneurysm Associated With Upregulation of Angiotensin-Converting Enzyme 2.

Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA). This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA. APPROACH AND RESULTS: Ace2 deletion in apolipoprotein-deficient mice (ApoE-/-Ace2-/y ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers. In humans, serum ACE2 activity was negatively associated with AAA diagnosis. ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors. AAA was more severe in ApoE-/-Ace2-/y mice compared with controls in 2 experimental models. Resveratrol (0.05/100-g chow) inhibited growth of pre-established AAAs in ApoE-/- mice fed high-fat chow and infused with angiotensin II continuously for 56 days. Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity. In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced. Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent. This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth. Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model.

Moran CS ，Biros E ，Krishna SM ，Wang Y ，Tikellis C ，Morton SK ，Moxon JV ，Cooper ME ，Norman PE ，Burrell LM ，Thomas MC ，Golledge J ... -  《-》