Faculty Bibliography

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.

Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

Purpose of Study Autism spectrum disorders (ASDs) are neurodevelopmental disorders with lifelong consequences and poorly understood pathophysiology. Dysregulated cholesterol metabolism is implicated in ASD etiology. Cholesterol is essential for neuroactive steroid production, myelin sheath formation, and normal brain development. Early postnatal or in utero exposure to the antiepileptic drug valproic acid (VPA), a branched short-chain fatty acid, causes autism-like neural and behavioral deficits in humans and rodents. This study examines the link between VPA and cholesterol deficit in cultured human neurons and microglia. Methods Used SHSY-5Y human neuroblastoma cells and HMC3 human microglial cells were exposed to VPA at 0, 250, 1000 and 5000 muM for 24h, N=3 per condition. Expression of critical genes that regulate cholesterol transport were quantified by RT-PCR using specific primers for each. These include the efflux proteins ABCA1, ABCG1, 27-hydroxylase (27-OHase) and 24-hydroxylase (24-OHase), and the influx scavenger receptor CD36 - all vital for brain cholesterol balance. Expression of these target genes was normalized to concurrently measured GAPDH mRNA levels. Summary of Results In SH-SY5Y neurons, VPA exposure caused a concentration-dependent increase in ABCA1 (P <0.001), ABCG1, 27-OHase (P <0.001) (figure 1), and CD36 (P=0.015). In HMC3, VPA exposure caused a concentration- dependent increase in ABCG1 (80-fold at highest dose, P<=0.001) and 24-OHase (P < 0.001) with a reduction in ABCA-1 (P=0.002) and an increase in CD36 (P<0.001). Conclusions This study shows that VPA has a dramatic hypocholesterolemic effect on two key cell types that compose the developing brain. The net impact of the changes observed in these cholesterol-related genes would be outflow and metabolism. Further, enhanced 27-OHase activity produces an oxysterol metabolite with neurotoxic effects that include downregulating synaptic proteins and decreasing neurite number and length. Together, our results suggest that VPA impairs brain cholesterol homeostasis. A better understanding of the involvement of cholesterol in the mechanisms by which VPA leads to ASDs may translate into novel preventative therapies for this serious disorder

The idea that trillions of bacteria inhabit our gut is somewhat unnerving, yet these bacteria may have a greater influence on our behavior than previously thought. Accumulating data strongly suggest that these gut commensal organisms have a strong inter-relationship with our brain and behavior, including cognitive function, mood, and personality. In this chapter, we discuss the role of the gut microbiome in the development of human personality, mood and mood disorders, and cognition, with a particular emphasis on the current consensus and controversies in the literature surrounding the behavioral effects of bioactive metabolites, microbial ratio shifts, and neurotransmitter synthesis facilitated by the microbiome.

Adenosine is an endogenous nucleoside with a short half-life that regulates many physiological functions involving the heart and cardiovascular system. Among the cardioprotective properties of adenosine are its ability to improve cholesterol homeostasis, impact platelet aggregation and inhibit the inflammatory response. Through modulation of forward and reverse cholesterol transport pathways, adenosine can improve cholesterol balance and thereby protect macrophages from lipid overload and foam cell transformation. The function of adenosine is controlled through four G-protein coupled receptors: A₁, A_2A, A_2B and A₃. Of these four, it is the A_2A receptor that is in a large part responsible for the anti-inflammatory effects of adenosine as well as defense against excess cholesterol accumulation. A_2A receptor agonists are the focus of efforts by the pharmaceutical industry to develop new cardiovascular therapies, and pharmacological actions of the atheroprotective and anti-inflammatory drug methotrexate are mediated via release of adenosine and activation of the A_2A receptor. Also relevant are anti-platelet agents that decrease platelet activation and adhesion and reduce thrombotic occlusion of atherosclerotic arteries by antagonizing adenosine diphosphate-mediated effects on the P2Y12 receptor. The purpose of this review is to discuss the effects of adenosine on cell types found in the arterial wall that are involved in atherosclerosis, to describe use of adenosine and its receptor ligands to limit excess cholesterol accumulation and to explore clinically applied anti-platelet effects. Its impact on electrophysiology and use as a clinical treatment for myocardial preservation during infarct will also be covered. Results of cell culture studies, animal experiments and human clinical trials are presented. Finally, we highlight future directions of research in the application of adenosine as an approach to improving outcomes in persons with cardiovascular disease.

OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Background andObjectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

BACKGROUND:Macrophage cholesterol efflux capacity has been identified as a predictor for cardiovascular disease. We assessed the relationship between adipocyte-derived extracellular vesicle microRNAs and macrophage cholesterol efflux capacity. METHODS:) for: (1) cholesterol efflux capacity and lipoprotein profiles; (2) adipocyte-derived extracellular vesicle microRNAs in serum; (3) the role of visceral adipose tissue extracellular vesicle in regulation of cholesterol efflux and cholesterol efflux gene expression in THP-1 macrophages in vitro. RESULTS:Efflux capacity was significantly associated with HDL (r = 0.30, p = 0.01) and LDL (r = 0.33, p = 0.005) particle size. Multivariate-analysis identified six microRNAs associated (p < 0.05) with cholesterol efflux capacity: miR-3129-5p (Beta = 0.695), miR-20b (0.430), miR9-5p (0.111), miR-320d (- 0.190), miR301a-5p (0.042), miR-155-5p (0.004). In response to increasing concentrations (1 μg/mL vs. 3 μg/mL) of VAT extracellular vesicle, cholesterol efflux (66% ± 10% vs. 49% ± 2%; p < 0.01) and expression of ABCA1 (FC = 1.9 ± 0.8 vs 0.5 ± 0.2; p < 0.001), CD36 (0.7 ± 0.4 vs. 2.1 ± 0.8, p = 0.02), CYP27A1 (1.4 ± 0.4 vs. 0.9 ± 0.5; p < 0.05), and LXRA (1.8 ± 1.1 vs. 0.5 ± 0.2; p < 0.05) was altered in THP-1 cells in vitro. CONCLUSION/CONCLUSIONS:Adipocyte-derived extracellular vesicle microRNAs may, in part, be involved macrophage cholesterol efflux regulation.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite multiple treatment options. In addition to elevated lipid levels, oxidative stress and inflammation are key factors driving atherogenesis and CVD. New strategies are required to mitigate risk and most urgently for statin-intolerant patients. The neuropeptide hormone oxytocin, synthesized in the brain hypothalamus, is worthy of consideration as a CVD ancillary treatment because it moderates factors directly linked to atherosclerotic CVD such as inflammation, weight gain, food intake and insulin resistance. Though initially studied for its contribution to parturition and lactation, oxytocin participates in social attachment and bonding, associative learning, memory and stress responses. Oxytocin has shown promise in animal models of atherosclerosis and in some human studies as well. A number of properties of oxytocin make it a candidate CVD treatment. Oxytocin not only lowers fat mass and cytokine levels, but also improves glucose tolerance, lowers blood pressure and relieves anxiety. Further, it has an important role in communication in the gut-brain axis that makes it a promising treatment for obesity and type 2 diabetes. Oxytocin acts through its receptor which is a class I G-protein-coupled receptor present in cells of the vascular system including the heart and arteries. While oxytocin is not used for heart disease at present, residual CVD risk remains in a substantial portion of patients despite multidrug regimens, leaving open the possibility of using the endogenous nonapeptide as an adjunct therapy. This review discusses the possible role for oxytocin in human CVD prevention and treatment.

BACKGROUND:Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder that increases the risk of developing cardiovascular disease. There is accumulating evidence that the RA disease state accelerates the formation of atherosclerotic plaques. Treatments for RA improve joint symptomatology and may reduce inflammation, but consideration of their effects on the cardiovascular system is generally low priority. OBJECTIVE:Since cardiovascular disease is the leading cause of mortality in RA patients, the impact of RA therapies on atherosclerosis is an area in need of attention and the focus of this review. RESULTS:The drugs used to treat RA may be analgesics, conventional disease-modifying anti-rheumatic drugs, and/or biologics, including antibodies against the cytokine tumor necrosis factor-α. Pain relievers such as non-selective non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors may adversely affect lipid metabolism and cyclooxygenase inhibitors have been associated with increased adverse cardiovascular events, such as myocardial infarction and stroke. Methotrexate, the anchor disease-modifying anti-rheumatic drug in RA treatment, has multiple atheroprotective advantages and is often combined with other therapies. Biologic inhibitors of tumor necrosis factor-α may be beneficial in preventing cardiovascular disease because tumor necrosis factor-α promotes initiation and progression of atherosclerosis. However, some studies show a worsening of the lipid profile in RA with blockade of this cytokine, leading to higher total cholesterol and triglycerides. CONCLUSION/CONCLUSIONS:Greater understanding of the pharmacologic activity of RA treatments on the atherosclerotic process may lead to improved care, addressing both damage to the joints and damage to the heart.