A New Mouse Model of Aortic Aneurysm Induced by Deoxycorticosterone Acetate or Aldosterone in the Presence of High Salt

The renin-angiotensin-aldosterone system (RAAS) is implicated in the etiologies of many cardiovascular diseases, including abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA). In particular, the infusion of angiotensin II (Ang II) in hyperlipidemia mice to induce AAA and TAA has been extensively used in the field, suggesting a critical role of Ang II in aortic aneurysm. In contrast, whether aldosterone (Aldo), a downstream effector of Ang II, is involved in aortic aneurysm is unknown. Here, we describe a new mouse model of AAA and TAA induced by subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets or infusion of Aldo using osmotic pumps to 10-month-old C57BL/6 male mice in the presence of high salt. The DOCA- or Aldo-salt-induced aortic aneurysm is dependent upon mineralocorticoid receptor activation but independent of Ang II and hypertension and exhibits several unique features that mimic human aortic aneurysm. This review aims to discuss the common animal models of AAA, TAA, and aortic dissection currently studied in the world with the most focus on the DOCA- or Aldo-salt mouse model of aortic aneurysm

Aboveground Biomass and Soil Moisture as Affected by Short-Term Grazing Exclusion in Eastern Alpine Meadows of the Qinghai-Tibet Plateau, China

Heavy grazing substantially influences grassland vegetation and animal nutrition on the Qinghai-Tibet plateau (Guo et al. 2003). Degradation is characterized by a reduction in vegetation height, reduced ground cover decrease in species diversity (Wang et al. 2007). The objective of this study was to determine the effects of short-term exclusion from grazing on aboveground herbage, forage nutritive value, and soil moisture in an alpine meadow in the eastern zone of the plateau. Three farms, applying different intensity of grazing over the summer months, were compared

iPLA2β Overexpression in Smooth Muscle Exacerbates Angiotensin II-Induced Hypertension and Vascular Remodeling

Calcium independent group VIA phospholipase A(2) (iPLA(2)β) is up-regulated in vascular smooth muscle cells in some diseases, but whether the up-regulated iPLA(2)β affects vascular morphology and blood pressure is unknown. The current study addresses this question by evaluating the basal- and angiotensin II infusion-induced vascular remodeling and hypertension in smooth muscle specific iPLA(2)β transgenic (iPLA(2)β-Tg) mice.Blood pressure was monitored by radiotelemetry and vascular remodeling was assessed by morphologic analysis. We found that the angiotensin II-induced increase in diastolic pressure was significantly higher in iPLA(2)β-Tg than iPLA(2)β-Wt mice, whereas, the basal blood pressure was not significantly different. The media thickness and media∶lumen ratio of the mesenteric arteries were significantly increased in angiotensin II-infused iPLA(2)β-Tg mice. Analysis revealed no difference in vascular smooth muscle cell proliferation. In contrast, adenovirus-mediated iPLA(2)β overexpression in cultured vascular smooth muscle cells promoted angiotensin II-induced [(3)H]-leucine incorporation, indicating enhanced hypertrophy. Moreover, angiotensin II infusion-induced c-Jun phosphorylation in vascular smooth muscle cells overexpressing iPLA2β to higher levels, which was abolished by inhibition of 12/15 lipoxygenase. In addition, we found that angiotensin II up-regulated the endogenous iPLA(2)β protein in-vitro and in-vivo.The present study reports that iPLA(2)β up-regulation exacerbates angiotensin II-induced vascular smooth muscle cell hypertrophy, vascular remodeling and hypertension via the 12/15 lipoxygenase and c-Jun pathways

Smooth Muscle-specific Expression of Calcium-independent Phospholipase A2 (iPLA2 ) Participates in the Initiation and Early Progression of Vascular Inflammation and Neointima Formation

Background: The role of iPLA 2 β as a regulator of inflammatory signaling and neointima formation is unknown. Result: Smooth muscle-specific expression of iPLA 2 β exacerbates proinflammatory cytokine production, macrophage infiltration, and neointima formation. Conclusion: Smooth muscle-specific iPLA 2 β participates in the initiation and early progression of vascular inflammation and neointima formation. Significance: iPLA 2 β may represent a novel therapeutic target for attenuating vascular inflammation and restenosis

Smooth-Muscle BMAL1 Participates in Blood Pressure Circadian Rhythm Regulation

As the central pacemaker, the suprachiasmatic nucleus (SCN) has long been considered the primary regulator of blood pressure circadian rhythm; however, this dogma has been challenged by the discovery that each of the clock genes present in the SCN is also expressed and functions in peripheral tissues. The involvement and contribution of these peripheral clock genes in the circadian rhythm of blood pressure remains uncertain. Here, we demonstrate that selective deletion of the circadian clock transcriptional activator aryl hydrocarbon receptor nuclear translocator-like (Bmal1) from smooth muscle, but not from cardiomyocytes, compromised blood pressure circadian rhythm and decreased blood pressure without affecting SCN-controlled locomotor activity in murine models. In mesenteric arteries, BMAL1 bound to the promoter of and activated the transcription of Rho-kinase 2 (Rock2), and Bmal1 deletion abolished the time-of-day variations in response to agonist-induced vasoconstriction, myosin phosphorylation, and ROCK2 activation. Together, these data indicate that peripheral inputs contribute to the daily control of vasoconstriction and blood pressure and suggest that clock gene expression outside of the SCN should be further evaluated to elucidate pathogenic mechanisms of diseases involving blood pressure circadian rhythm disruption

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes

Identification of a cAMP-response element in the regulator of G-protein signaling-2 (RGS2) promoter as a key cis-regulatory element for RGS2 transcriptional regulation by angiotensin II in cultured vascular smooth muscles

Mice deficient in regulator of G-protein signaling-2 (RGS2) have severe hypertension, and RGS2 genetic variations occur in hypertensive humans. A potentially important negative feedback loop in blood pressure homeostasis is that angiotensin II (Ang II) increases vascular smooth muscle cell (VSMC) RGS2 expression. We reported that Group VIA phospholipase A2 (iPLA2β) is required for this response (Xie, Z., Gong, M. C., Su, W., Turk, J., and Guo, Z. (2007) J. Biol. Chem. 282, 25278–25289), but the specific molecular causes and consequences of iPLA2β activation are not known. Here we demonstrate that both protein kinases C (PKC) and A (PKA) participate in Ang II-induced VSMC RGS2 mRNA up-regulation, and that actions of PKC and PKA precede and follow iPLA2β activation, respectively. Moreover, we identified a conserved cAMP-response element (CRE) in the murine RGS2 promoter that is critical for cAMP-response element-binding protein (CREB) binding and RGS2 promoter activation. Forskolin-stimulated RGS2 mRNA up-regulation is inhibited by CREB sequestration or specific disruption of the CREB-RGS2 promoter interaction, and Ang II-induced CREB phosphorylation and nuclear localization are blocked by iPLA2β pharmacologic inhibition or genetic ablation. Ang II-induced intracellular cyclic AMP accumulation precedes CREB phosphorylation and is diminished by inhibiting iPLA2, cyclooxygenase, or lipoxygenase. Moreover, three single nucleotide polymorphisms identified in hypertensive patients are located in the human RGS2 promoter CREB binding site. Point mutations corresponding to these single nucleotide polymorphisms interfere with stimulation of human RGS2 promoter activity by forskolin. Our studies thus delineate a negative feedback loop to attenuate Ang II signaling in VSMC with potential importance in blood pressure homeostasis and the pathogenesis of human essential hypertension