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

Role of sympathetic pathway in light-phase time-restricted feeding-induced blood pressure circadian rhythm alteration

Disruption of blood pressure (BP) circadian rhythm, independent of hypertension, is emerging as an index for future target organ damage and is associated with a higher risk of cardiovascular events. Previous studies showed that changing food availability time alters BP rhythm in several mammalian species. However, the underlying mechanisms remain largely unknown. To address this, the current study specifically investigates (1) the relationship between rhythms of food intake and BP in wild-type mice; (2) effects of light-phase time-restricted feeding (TRF, food only available during light-phase) on BP circadian rhythm in wild-type and diabetic db/db mice; (3) the roles of the autonomic system and clock gene in light-phase TRF induced changes in BP circadian rhythm. Food intake and BP of C57BL/6J and db/db mice were simultaneously and continuously recorded using BioDAQ and telemetry systems under ad libitum or light-phase TRF. Per2 protein daily oscillation was recorded in vivo by IVIS spectrum in mPer2Luc mice. Autonomic nerve activity was evaluated by heart rate variability, baroreflex, urinary norepinephrine (NE) and epinephrine (Epi) excretion, and mRNA expressions of catecholamines biosynthetic and catabolic enzymes, and alpha-adrenergic receptors in mesenteric resistance arteries. We found that in wild-type mice, the BP level was correlated with the food intake temporally across the 24 h. Reversing the feeding time by imposing light-phase TRF resulted in reverse or inverted BP dipping. Interestingly, the net changes in food intake were correlated with the net alteration in BP temporally under light-phase TRF. In db/db mice, light-phase TRF worsened the existing non-dipping BP. The food intake and BP circadian rhythm changes were associated with alterations in Per2 protein daily oscillation and the time-of-day variations in heart rate variability, baroreflex, and urinary excretion of NE and Epi, and increased mRNA expression of Slc6a2 (encoding NE transporter) and Adra1d (encoding alpha-adrenergic receptor 1d) in the mesenteric resistance arteries, indicating the sympathetic nervous system (SNS) was modulated after light-phase TRF. Collectively, our results demonstrated that light-phase TRF results in reverse dipping of BP in wild-type and diabetic db/db mice and revealed the potential role of the sympathetic pathway in light-phase TRF-induced BP circadian rhythm alteration

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

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

Characterization of GLP-1 Receptor in Flox & Knockout Mice

Type 2 Diabetes mellitus (T2DM) is one of the most prevalent and costly diseases concerning modern society, characterized by impaired insulin action, inducing chronic hyperglycemia. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an emerging class of drugs proven extremely effective in treating T2DM and obesity. GLP-1 is a peptide secreted by enteroendocrine L cells along the digestive tract. Secreted GLP-1 acts on the pancreas to stimulate insulin, inhibit glucagon secretion, and suppress appetite. Challenges in GLP-1R research are antibody specificity and inconsistent effects of knocking out GLP-1R globally. This study aims to examine the efficacy of tamoxifen-induced knockout of GLP1-R on protein, mRNA, and DNA levels. Breeding of Glp-1r loxP-flanked (flox) mice with tamoxifen-inducible ubiquitous Cre (UBC-Cre-ERT2) mice on a C57Bl/6 genetic background results in Cre-mediated deletion of Glp-1r in widespread tissues. The flox Glp-1r sequence is greater than 6000 bp, but after cleavage is 387 bp. The 30 second annealing step in the PCR protocol allows only for amplification of sequences less than 500 bp. Results reflected successful cleavage of Glp-1r. Western blotting identified that, among the three GLP-1R antibodies tested, the ProteinTech antibody most efficaciously detects GLP-1R, showing significant difference between GLP-1R flox and KO mice in duodenum (p Results support effectiveness of tamoxifen-induced GLP-1R knockout in duodenum and hypothalamus. GLP-1R KO in the liver demonstrates low success, potentially attributable to uneven Cre expression. In the future, we hope this novel mouse model may be used for GLP-1R experiments examining its relationship to comorbidities of T2D

Application of Blockchain Technology in Environmental Health: Literature Review and Prospect of Visualization Based on CiteSpace

Blockchain technology and its applications have recently become a research hotspot. Its three core technologies, distributed ledger, smart contract, and consensus mechanism, provide trust-enhancing features such as tamper-proof records, full traceability, and data decentralization for a wide range of applications. This paper investigates the use of blockchain technology in environmental health. It investigates indicators such as the number of articles published, author collaboration network, research institution network, and keyword co-occurrence in this field between 2014 and 2021. It describes and analyzes the development and connotations of these indicators. Many scholars have conducted in-depth studies on blockchain in various areas. Still, there are few cross-over studies on environmental health and a lack of cross-over studies on technology application in multiple fields. The current study investigates the evolution of research on the application of blockchain technology in environmental health, as well as potential development patterns and research trends, to provide a theoretical foundation for the application and sustainability of blockchain technology in this field