Vitamin D attenuates HMGB1-mediated neointimal hyperplasia after percutaneous coronary intervention in swine.

Intracoronary stenting is a common procedure in patients with coronary artery disease (CAD). Stent deployment stretches and denudes the endothelial layer, promoting a local inflammatory response, resulting in neointimal hyperplasia. Vitamin D deficiency associates with CAD. In this study, we examined the association of vitamin D status with high mobility group box 1 (HMGB1)-mediated pathways (HMGB1, receptor for advanced glycation end products [RAGE], and Toll-like receptor-2 and -4 [TLR2 and TLR4]) in neointimal hyperplasia in atherosclerotic swine following bare metal stenting. Yucatan microswine fed with a high-cholesterol diet were stratified to receive vitamin D-deficient (VD-DEF), vitamin D-sufficient (VD-SUF), and vitamin D-supplemented (VD-SUP) diet. After 6 months, PTCA (percutaneous transluminal balloon angioplasty) followed by bare metal stent implantation was performed in the left anterior descending (LAD) artery of each swine. Four months following coronary intervention, angiogram and optical coherence tomography (OCT) were performed and swine euthanized. Histology and immunohistochemistry were performed in excised LAD to evaluate the expression of HMGB1, RAGE, TLR2, and TLR4. OCT analysis revealed the greatest in-stent restenosis area in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. The protein expression of HMGB1, RAGE, TLR2, and TLR4 was significantly higher in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. Vitamin D deficiency was associated with both increased in-stent restenosis and increased HMGB1-mediated inflammation noted in coronary arteries following intravascular stenting. Inversely, vitamin D supplementation was associated with both a decrease in this inflammatory profile and in neointimal hyperplasia, warranting further investigation for vitamin D as a potential adjunct therapy following coronary intervention.

An update on PTEN modulators - a patent review.

Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued. Areas covered: Here the authors provide recent updates to their previous publication on 'PTEN modulators: A patent review', and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson's disease, Alzheimer's disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn's disease, and several cancer types. Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.

Modulation of Cathepsin L Expression in the Coronary Arteries of Atherosclerotic Swine.

INTRODUCTION: Neointimal hyperplasia (NIH) and restenosis after percutaneous transluminal coronary angioplasty (PTCA) and intravascular stenting remain a problem on a long-term basis by causing endothelial denudation and damage to the intima and media. Vascular sterile inflammation has been attributed to the formation of NIH. Cathepsin L (CTSL), a lysosome protease, is associated with diet-induced atherogenesis. Vitamin D regulates the actions and regulatory effects of proteases and protease inhibitors in different cell types. Objectives of this study are to evaluate the modulatory effect of vitamin D on CTSL activity in post-PTCA coronary arteries of atherosclerotic swine. METHODS: Yucatan microswine were fed with high-cholesterol atherosclerotic diets. The swine were stratified to receive three diets: (1) vitamin D-deficient diet, (2) vitamin D-sufficient diet, and (3) vitamin D-supplement diet. After 6 mo, PTCA was performed in the left circumflex coronary artery (LCx). After 1 y, angiography and optical coherence tomography imaging were performed, and swine was euthanized. Coronary arteries were embedded in paraffin. Tissue sections were stained with hematoxylin and eosin. Expression of Ki67 and CTSL were evaluated by immunofluorescence. RESULTS: Increased number of Ki67 + cells were observed in the postangioplasty LCx in vitamin D-deficient compared with vitamin D-sufficient or vitamin D-supplemented swine. Notably, the expression of CTSL was significantly increased in postangioplasty LCx of vitamin D-deficient swine compared with the vitamin D-sufficient or vitamin D-supplemented animal groups. CONCLUSIONS: Increased expression of CTSL correlates with the formation of NIH in the PTCA-injured coronary arteries. However, in the presence of sufficient or supplemented levels of vitamin D in the blood, CTSL expression was significantly reduced.

Pro-inflammatory and pro-resolving mechanisms in the immunopathology of arteriovenous fistula maturation.

Introduction: With high rates of arteriovenous fistula (AVF) failure, there is a continued need to predict other factors and mechanisms associated with maturation deficits. Given the central association of inflammation with AVF failure, with neointimal hyperplasia (NIH) as one such mechanism, inflammation must be considered in two endogenous ways, either pro-inflammatory or pro-resolving, resulting in inward or outward vascular remodeling. Areas covered: This review summarizes and critically evaluates the preclinical and interventional data underlying AVF failure in attempts to elucidate the necessary balance between inflammation and its resolution. Expert opinion: Understanding the pro-inflammatory and pro-resolving mechanisms underlying inward and outward vascular remodeling and NIH prevention with AVF maturation is a necessary effort to develop key diagnostic and therapeutic interventions towards the ongoing issue of long-term AVF patency. The ability for clinical application has progressed but is limited to the identification of key targets and pathways with little understanding of how they are related synergistically or antagonistically. Likewise, the balance between acute inflammation and pro-resolution requires pertinent temporal considerations necessary for timely therapeutic application and predictive measurement.

Vitamin D and macrophage polarization in epicardial adipose tissue of atherosclerotic swine.

Vitamin D functions as a potent immunomodulator by interacting with many immune cells however, its role in regulating inflammation in the epicardial adipose tissue (EAT) is unclear. In the EAT of atherosclerotic microswine that were fed with deficient, sufficient or supplemented levels of vitamin D, we evaluated the phenotype of the macrophages. Vitamin D treatment was continued for 12 months and serum 25(OH)D levels were measured regularly. Infiltration of M1/M2 macrophage was investigated by immunostaining for CCR7 and CD206, respectively in conjunction with a pan macrophage marker CD14. Significant difference in the number of CCR7+ cells was observed in the EAT from vitamin D-deficient swine compared to vitamin D-sufficient or -supplemented swine. Expression of CD206 correlated with high levels of serum 25(OH)D indicating a significant increase in M2 macrophages in the EAT of vitamin D-supplemented compared to -deficient swine. These findings suggest that vitamin D-deficiency exacerbates inflammation by increasing pro-inflammatory M1 macrophages, while vitamin D-supplementation attenuates the inflammatory cytokines and promotes M2 macrophages in EAT. This study demonstrates the significance of vitamin D mediated inhibition of macrophage mediated inflammation in the EAT during coronary intervention in addition to its immunomodulatory role. However, additional studies are required to identify the cellular mechanisms that transduce signals between macrophages and smooth muscle cells during restenosis in the presence and absence of vitamin D.

TREM-1; Is It a Pivotal Target for Cardiovascular Diseases?

Cardiovascular diseases (CVDs) are as menacing as ever and still continue to kill adults worldwide, notwithstanding tremendous efforts to decrease their consequent mortality and morbidity. Lately, a growing body of research indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptors expressed on myeloid cells-1 (TREM-1) was shown to induce and amplify the inflammation in both acute and chronic disease' pathogenesis and progression, which hence makes it one of the most important complication factors of CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications, and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We critically analyzed and summarized our findings and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management, and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions, such as acute myocardial infarction (AMI) and atherosclerosis. Although most therapeutic approaches are yet to be elucidated, our present research outcome displays a promising future to utilizing the TREM-1 pathway as a potential target for understanding and managing CVDs.

Inhibition of DNA methyltransferase-1 instigates the expression of DNA methyltransferase-3a in angioplasty-induced restenosis.

Increased expression of DNA methyltransferase-1 (DNMT1) associates with the progression of many human diseases. Because DNMT1 induces cell proliferation, drugs that inhibit DNMT1 have been used to treat proliferative diseases. Because these drugs are nonspecific inhibitors of DNMT1, subsidiary events or the compensatory mechanisms that are activated in the absence of DNMT1 limit their therapeutic application. Here, we studied the molecular mechanisms that occur during angioplasty-induced restenosis and found that DNMT1 inhibition in both in vitro and in vivo approaches resulted in the induction of DNA methyltransferase-3a (DNMT3a) expression. In vascular smooth muscle cells (VSMCs), the microRNA hsa-miR-1264 mimic, specifically inhibiting DNMT1, induced nuclear expression of DNMT3a. On the contrary, there was no induced expression of DNMT3a in VSMCs that were transfected with hsa-miR-1264 inhibitor. Further, ectopic expression of suppressor of cytokine signaling 3 (SOCS3) through adeno-associated virus (AAV)-mediated gene delivery in the coronary arteries of Yucatan microswine showed inhibition of both DNMT1 and DNMT3a in vivo. These findings show the existence of an inter-regulatory mechanism between DNMT1 and DNMT3a where, in the absence of DNMT1, induction of DNMT3a compensates for the loss of DNMT1 functions, suggesting that the inhibition of both DNMT1 and DNMT3a are required to prevent restenosis.

Escitalopram-Induced Amenorrhea and False Positive Urine Pregnancy Test.

Escitalopram is a selective serotonin reuptake inhibitor antidepressant approved by the Food and Drug Administration for the treatment of major depressive disorder and generalized anxiety disorder. A 34-year-old female patient with major depressive disorder developed amenorrhea and had a false-positive urine pregnancy test after initiation of escitalopram treatment. To our knowledge, no published case report of amenorrhea and false-positive urine pregnancy tests in women taking escitalopram exists. This case report suggests that women of child-bearing age should be carefully monitored for amenorrhea while they are on an antidepressant treatment regimen.

Urinary Incontinence due to Overactive Detrusor Muscle: A Rare Side Effect of Venlafaxine.

We report a case of reemergence of urinary incontinence (UI) in a patient with benign prostatic hyperplasia (BPH) after starting treatment with venlafaxine who was stabilized on tamsulosin and finasteride for about 6 years. A 66-year-old Caucasian male with prior history of major depressive disorder developed UI within a week of starting venlafaxine 75 mg per day. He described symptoms in the form of involuntary leakage of urine both during the day and at night. His symptoms of UI resolved after stopping the venlafaxine. To the best of our knowledge, there are only four case reports of venlafaxine induced urinary incontinence which have been published.