ABSTRACT
AIMS: Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. METHODS AND RESULTS: Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. CONCLUSION: Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.
Subject(s)
Aorta, Abdominal/drug effects , Aortic Aneurysm, Abdominal/prevention & control , NAD/metabolism , Niacin/pharmacology , Niacinamide/pharmacology , Receptors, G-Protein-Coupled/metabolism , Angiotensin II , Animals , Aorta, Abdominal/metabolism , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/chemically induced , Aortic Aneurysm, Abdominal/metabolism , Aortic Aneurysm, Abdominal/pathology , Calcium Chloride , Cells, Cultured , Dilatation, Pathologic , Disease Models, Animal , Male , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/genetics , Receptors, LDL/genetics , Receptors, LDL/metabolism , Signal Transduction , Sirtuin 1/metabolismABSTRACT
BACKGROUND: Cognitive training is beneficial in various clinical settings, although its perioperative feasibility and impact remain unknown. The objective of this pilot study was to determine the feasibility of home-based cognitive prehabilitation before major surgery in older adults. MATERIALS AND METHODS: Sixty-one patients were enrolled, randomized, and allocated to either a home-based preoperative cognitive training regimen or no training before surgery. Outcomes included postoperative delirium incidence (primary outcome; assessed with the 3D-Confusion Assessment Method), perioperative cognitive function based on NIH Toolbox measures, hospital length of stay, and physical therapy session participation. Reasons for declining enrollment were reported, as were reasons for opting out of the training program. RESULTS: Postoperative delirium incidence was 6 of 23 (26%) in the prehabilitation group compared with 5 of 29 (17%) in the control group (P=0.507). There were no significant differences between groups in NIH Toolbox cognitive function scoring, hospital length of stay, or physical therapy participation rates. Study feasibility data were also collected and reported. The most common reasons for declining enrollment were lack of computer access (n=19), time commitment (n=9), and feeling overwhelmed (n=9). In the training group, only 5 of 29 (17%) included patients were able to complete the prescribed 7 days of training, and 14 of 29 (48%) opted out of training once home. Most common reasons were feeling overwhelmed (n=4) and computer difficulties (n=3). CONCLUSIONS: Short-term, home-based cognitive training before surgery is unlikely to be feasible for many older patients. Barriers to training include feeling overwhelmed, technical issues with training, and preoperative time commitment.
Subject(s)
Cognition Disorders/prevention & control , Delirium/prevention & control , Home Care Services , Postoperative Complications/prevention & control , Preoperative Care/methods , Aged , Cognition Disorders/psychology , Delirium/psychology , Feasibility Studies , Female , Humans , Incidence , Length of Stay , Male , Middle Aged , Neuropsychological Tests , Patient Dropouts , Physical Therapy Modalities , Pilot Projects , Postoperative Complications/psychology , Single-Blind Method , Treatment OutcomeABSTRACT
Obesity has increased dramatically in the last few decades and affects over one third of the adult US population. The economic effect of obesity in 2005 reached a staggering sum of $190.2 billion in direct medical costs alone. Obesity is a major risk factor for a wide host of diseases. Historically, little was known regarding adipose and its major and essential functions in the body. Brown and white adipose are the two main types of adipose but current literature has identified a new type of fat called brite or beige adipose. Research has shown that adipose depots have specific metabolic profiles and certain depots allow for a propensity for obesity and other related disorders. The goal of this protocol is to provide researchers the capacity to identify and excise adipose depots that will allow for the analysis of different factorial effects on adipose; as well as the beneficial or detrimental role adipose plays in disease and overall health. Isolation and excision of adipose depots allows investigators to look at gross morphological changes as well as histological changes. The adipose isolated can also be used for molecular studies to evaluate transcriptional and translational change or for in vitro experimentation to discover targets of interest and mechanisms of action. This technique is superior to other published techniques due to the design allowing for isolation of multiple depots with simplicity and minimal contamination.
Subject(s)
Adipose Tissue, Brown/anatomy & histology , Adipose Tissue, Brown/surgery , Adipose Tissue, White/anatomy & histology , Adipose Tissue, White/surgery , Mice/anatomy & histology , Mice/surgery , Surgical Procedures, Operative/veterinary , Animals , Female , MaleABSTRACT
Cardiovascular disease is a broad term describing disease of the heart and/or blood vessels. The main blood vessel supplying the body with oxygenated blood is the aorta. The aorta may become affected in diseases such as atherosclerosis and aneurysm. Researchers investigating these diseases would benefit from direct observation of the aorta to characterize disease progression as well as to evaluate efficacy of potential therapeutics. The goal of this protocol is to describe proper isolation and excision of the aorta to aid investigators researching cardiovascular disease. Isolation and excision of the aorta allows investigators to look at gross morphometric changes as wells as allowing them to preserve and stain the tissue to look at histologic changes if desired. The aorta may be used for molecular studies to evaluate protein and gene expression to discover targets of interest and mechanisms of action. This technique is superior to imaging modalities as they have inherent limitations in technology and cost. Additionally, primary isolated cells from a freshly isolated and excised aorta can allowing researchers to perform further in situ and in vitro assays. The isolation and excision of the aorta has the limitation of having to sacrifice the animal however, in this case the benefits outweigh the harm as it is the most versatile technique in the study of aortic disease.
