Angiotensin II facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of APE/Ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1.

Angiotensin II (Ang II) is implicated in the development of cardiovascular disorders including hypertension and atherosclerosis. However, the role of Ang II in the interaction between apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) and sphingosine-1-phosphate (S1P) signals in relation to vascular disorders remains to be clarified. This study aimed to determine whether APE/Ref-1 plays a role in epigenetic regulation of the S1P receptor (S1PR) in response to Ang II in vascular smooth muscle cell (VSMC) migration and vascular neointima formation.

DJ-1 is involved in epigenetic control of sphingosine-1-phosphate receptor expression in vascular neointima formation.

DJ-1 and sphingosine-1-phosphate (S1P) receptors (S1PRs) are implicated in the control of physiology and pathophysiology of cardiovascular systems such as blood pressure, atherosclerosis, and restenosis. Here, we investigated whether DJ-1 with antioxidant function participates in the regulation of S1PR1 and S1PR2 expression in vascular smooth muscle cells (VSMCs) and whether this response is related to vascular neointima formation. In vitro studies used cellular migration assay, western blot, reverse transcriptase and real-time PCR analysis, and immunocytochemistry.

Carvacrol inhibits atherosclerotic neointima formation by downregulating reactive oxygen species production in vascular smooth muscle cells.

Objective: Carvacrol (2-methyl-5-(1-methylethyl) phenol), a cyclic monoterpene, exerts protective activities in a variety of pathological states including tumor growth, inflammation, and oxidative stress. However, it is unknown whether carvacrol affects events in vascular cells during the development of atherosclerotic neointima. We investigated the effects of carvacrol on the migration and proliferation of rat aortic smooth muscle cells (RASMCs) and on vascular neointima formation.

Ketoconazole induces apoptosis in rat cardiomyocytes through reactive oxygen species-mediated parkin overexpression.

Azole antifungals such as ketoconazole are generally known to induce a variety of heart function side effects, e.g., long-QT syndrome and ventricular arrhythmias.

DJ-1 regulates the expression of renal (pro)renin receptor via reactive oxygen species-mediated epigenetic modification.

Background: DJ-1 protein plays multifunctional roles including transcriptional regulation and scavenging oxidative stress; thus, it may be associated with the development of renal disorders. We investigated whether DJ-1 protein regulates the expression of (pro)renin receptor (PRR), a newly identified member of renin-angiotensin system.

Methods: The levels of mRNA and protein were determined by real-time PCR and western blot, respectively.

DJ-1 protein regulates CD3+ T cell migration via overexpression of CXCR4 receptor.

Objective: DJ-1-a multifunctional protein responding to oxidative stress-is a possible regulator of the inflammatory response that plays an important role in atherosclerosis. Stromal cell-derived factor (SDF)-1 and its receptor, chemokine receptor type 4 (CXCR4), have been implicated in the recruitment of inflammatory cells during atherosclerosis. Here we investigated the hypothesis that DJ-1 protein might participate in CD3+ T cell functions in response to SDF-1 and contribute to the pathogenesis of atherosclerosis.

DJ-1/park7 modulates vasorelaxation and blood pressure via epigenetic modification of endothelial nitric oxide synthase.

Aims: DJ-1/park7, a multifunctional protein, may play essential roles in the vascular system. However, the function of DJ-1/park7 in vascular contractility has remained unclear. The present study was designed to investigate whether the DJ-1/park7 is involved in the regulation of vascular contractility and systolic blood pressure (SBP).

Recruitment of specificity protein 1 by CpG hypomethylation upregulates Na⁺-K⁺-2Cl⁻ cotransporter 1 in hypertensive rats.

Objectives: Promoter hypomethylation leads to upregulation of Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) in the spontaneously hypertensive rat (SHR). We hypothesized that recruitment of Specificity Protein 1 (Sp1) by CpG hypomethylation would result in upregulation of Na⁺-K⁺-2Cl⁻ cotransporter 1 in hypertensive rats.

Methods: Sham-operated Wistar-Kyoto (WKY) rats (sham) and angiotensin II (Ang II)-infused WKY rats, as well as SHRs, were used in this study.

Compound K, an intestinal metabolite of ginsenosides, inhibits PDGF-BB-induced VSMC proliferation and migration through G1 arrest and attenuates neointimal hyperplasia after arterial injury.

Objective: Compound K (CK), an intestinal metabolite of ginsenosides, has pharmacological properties such as anti-angiogenesis, anti-inflammation, anti-platelet and anti-cancer activities. In the present study, we investigated the inhibitory effect of CK on vascular smooth muscle cell (VSMC) proliferation and migration in vitro and neointima formation in a rat carotid artery injury model.

Results: CK significantly inhibited both the proliferation and migration of PDGF-BB-stimulated VSMCs in a concentration-dependent manner.

Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension.

Rationale: Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate-induced hypertensive rats and spontaneously hypertensive rats. However, the molecular mechanism remains elusive.

Objective: We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats.

DJ-1/park7 protects against neointimal formation via the inhibition of vascular smooth muscle cell growth.

Aims: DJ-1/park7 is a ubiquitously expressed multifunctional protein that plays essential roles in a variety of cells. However, its function in the vascular system has not been determined. We investigated the protective roles of DJ-1/park7 in vascular disorders, especially in neointimal hyperplasia.

Proteomic analysis of colonic mucosal tissue from tuberculous and ulcerative colitis patients.

Changes in the expression profiles of specific proteins leads to serious human diseases, including colitis. The proteomic changes related to colitis and the differential expression between tuberculous (TC) and ulcerative colitis (UC) in colon tissue from colitis patients has not been defined. We therefore performed a proteomic analysis of human TC and UC mucosal tissue.

Upregulation of the Na(+)-K(+)-2Cl(-) cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats.

The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in diverse models of hypertension. We hypothesized that NKCC1 is upregulated via histone modification in the aortas of angiotensin II (Ang II)-induced hypertensive rats. An osmotic mini-pump containing Ang II was implanted in the subcutaneous tissues of the backs of Sprague-Dawley (SD) rats for 7 days.

Tissue-specific upregulation of angiotensin-converting enzyme 1 in spontaneously hypertensive rats through histone code modifications.

The renin-angiotensin system has been implicated in the development of hypertension and damages several organs. The expressions of the components of a local renin-angiotensin system (RAS) in the hypertensive rats differ from those of the normotensive rats. We hypothesized that local tissue-specific upregulation of angiotensin-converting enzyme 1 (ACE1) in hypertension is caused by epigenetic changes.

Enrichment of (pro)renin receptor promoter with activating histone codes in the kidneys of spontaneously hypertensive rats.

Background: The (pro)renin receptor [(P)RR] non-proteolytically, through conformational change, activates prorenin which can convert angiotensinogen to angiotensin I in addition to the classic conversion of angiotensinogen to angiotensin I by circulating renin. Since renal (P)RR is upregulated in hypertension and implicated in the pathogenesis of malignant hypertension, we hypothesized that (pro)renin receptor promoter is enriched with activating histone codes in the kidney of spontaneously hypertensive rats (SHR).

Methods: The mRNA and protein expression levels were measured by real-time polymerase chain reaction (PCR) and western blot, respectively.

Disruption of tracheobronchial airway growth following postnatal exposure to ozone and ultrafine particles.

This study examined airway structure changes in adult rats after a long recovery period due to sub-chronic juvenile exposure to ozone and ultrafine particles that have a high organic fraction. Neonatal male Sprague-Dawley rats were exposed during lung development to 3 cycles of 0.5 ppm ozone from postnatal day 7 through 25.

Simulated annealing implementation with shorter Markov chain length to reduce computational burden and its application to the analysis of pulmonary airway architecture.

A new way to implement the Simulated Annealing (SA) algorithm was developed and tested that improves computation performance by using shorter Markov chain length (inner iterations) and repeating the entire SA process until the final function value meets the solution criterion. The new approach coupled with the adaptive neighborhood method was tested on the Rosenbrock function in 4 and 13 dimensions. This implementation significantly improved the computation speed without degrading solution quality.

Postnatal growth of tracheobronchial airways of Sprague-Dawley rats.

Rats are widely used for the studies of pulmonary toxicology in both juveniles and adults. To facilitate such studies, investigators have developed models of lung architecture based on manual or computerized airway measurements. However, postnatal growth of conducting airways of rat lungs has never been reported.

Detecting alterations in pulmonary airway development with airway-by-airway comparison.

Neonatal and postnatal exposures to air pollutants have adverse effects on lung development resulting in airway structure changes. Usually, generation-averaged analysis of airway geometric parameters is employed to differentiate between pulmonary airway trees. However, this method is limited, especially for monopodial branching trees such as in rat airways, because both quite proximal and less proximal airways that have very different structure and function may be in the same generation.

Small particles disrupt postnatal airway development.

Increasing numbers of epidemiologic studies associate air pollution exposure in children with decreased lung function development. The objective of this study was to examine the effects of exposure to combustion-generated fine [230 and 212 nm number mean aerodynamic particle diameter (NMAD)] to ultrafine (73 nm NMAD) particles differing in elemental (EC) and organic (OC) carbon content on postnatal airway development in rats. Neonatal Sprague-Dawley rats were exposed from postnatal day 7 through 25, and lung function and airway architecture were evaluated 81 days of age.

Promoter hypomethylation upregulates Na+-K+-2Cl- cotransporter 1 in spontaneously hypertensive rats.

The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is one of several transporters that have been implicated for development of hypertension since NKCC1 activity is elevated in hypertensive aorta and vascular contractions are inhibited by bumetanide, an inhibitor of NKCC1. We hypothesized that promoter hypomethylation upregulates the NKCC1 in spontaneously hypertensive rats (SHR). Thoracic aortae and mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction.

Pulmonary architecture in the conducting regions of six rats.

Rats are widely used for studies of pulmonary toxicology and lung disease. Several studies suggest nominal geometric parameters describing the architecture of the rat airway. However, intersubject variance has never been reported due to the huge effort and time to take these manual measurements.

Expiration rate drives human airway design.

Analyses of human airway architecture based on calculations of airflow resistance or energy dissipation suggest that the branching pattern is not optimized for minimizing energy loss by flow dissipation during respiration. Airway flow dissipates only a few percent of the total body work during normal breathing, so branching patterns deviate from minimum energy loss to also optimize other physiological needs. Studies of airway performance often record some measure of expiration, such as FEV1 (Forced Expiratory Volume in 1s), because airway constriction during expiration limits the rate of rapid respiration.

Bifurcation model for characterization of pulmonary architecture.

A flexible mathematical model of an asymmetric bronchial airway bifurcation is presented. The bifurcation structure is automatically determined after the user specifies geometric parameters: radius of parent airway, radii of daughter airways, radii of curvature of the daughter branch toroids, bifurcation angles, and radius of curvature of carina ridge. Detailed shape in the region where the three airways merge is defined by several explicit functions and can be changed with ease in accordance with observed lung structure.