• aortic dissection
• cell death
• chemokines
• hypertension
• inducible nitric oxide synthases
• mechanical stretch
• vascular smooth muscle cell

• JP 20K07073 JSPS KAKENHI

• Neointima
• Phosphodiesterase
• SMC
• Smooth muscle cell
• cGMP

• Animals
• Bromodeoxyuridine/metabolism
• Bromodeoxyuridine/pharmacology
• Cell Proliferation
• Cells, Cultured
• Cyclic GMP/metabolism
• Cyclic GMP-Dependent Protein Kinase Type I/metabolism
• Cyclin D1/metabolism
• Endothelial Cells/metabolism
• Guanylate Cyclase/metabolism
• Guanylate Cyclase/pharmacology
• Humans
• Hyperplasia/metabolism
• Hyperplasia/pathology
• Mice
• Muscle, Smooth, Vascular/metabolism
• Myocytes, Smooth Muscle/metabolism
• Phosphoric Diester Hydrolases/metabolism
• RNA, Messenger/metabolism
• Vascular Remodeling
• Vascular System Injuries/drug therapy
• Vascular System Injuries/genetics
• Vascular System Injuries/metabolism

• R01 HL122686 NHLBI NIH HHS
• R01 HL134910 NHLBI NIH HHS
• R01 HL139794 NHLBI NIH HHS
• R01 HL154318 NHLBI NIH HHS
• National Institute of Health
• American Heart Association

• Angiotensin-Converting Enzyme 2/genetics
• Angiotensin-Converting Enzyme 2/metabolism
• Apoptosis
• Carbazoles/pharmacology
• Cell Differentiation
• Cell Hypoxia
• Cell Survival
• Cells, Cultured
• Computational Biology
• Female
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Metabolic Networks and Pathways/drug effects
• Nitric Oxide Synthase Type III/metabolism
• Pulmonary Alveoli/drug effects
• Pulmonary Alveoli/injuries
• Pulmonary Alveoli/metabolism
• Pulmonary Surfactants/metabolism
• Respiratory Distress Syndrome, Newborn/etiology
• Respiratory Distress Syndrome, Newborn/metabolism
• Respiratory Distress Syndrome, Newborn/prevention & control
• Sirtuin 1/antagonists & inhibitors
• Sirtuin 1/metabolism
• Up-Regulation

• apoptosis
• cartilage
• cell death
• ectopic mineralization
• extracellular matrix
• vascular tissue

• Animals
• Apoptosis
• Calcinosis/pathology
• Cartilage/pathology
• Extracellular Matrix/pathology
• Humans
• Mitochondria/pathology
• Oxidative Stress

• NOS
• cell death
• hypertension
• stretch
• vascular smooth muscle cell

• Animals
• Aorta/cytology
• Aorta/enzymology
• Gene Expression Regulation, Enzymologic
• Male
• Mechanotransduction, Cellular
• Muscle, Smooth, Vascular/cytology
• Muscle, Smooth, Vascular/enzymology
• Myocytes, Smooth Muscle/cytology
• Myocytes, Smooth Muscle/enzymology
• Nitric Oxide Synthase Type II/biosynthesis
• Rats
• Rats, Sprague-Dawley
• Stress, Mechanical
• Up-Regulation

To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside.

Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis.

Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups.

The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

• Apoptosis
• Biotin
• Coronary Artery Bypass
• Diabetes Mellitus
• Diltiazem
• Hematoxylin
• Mammary Arteries
• Vasodilatador Agents

Angiotensin II (Ang II) is known to promote proliferation of vascular smooth muscle cells (VSMCs) in vascular remodeling, but whether it has an anti-apoptotic effect needs to be explored. Neuregulin-1 (NRG-1) as a member of the epidermal growth factor family was reported to suppress the proliferation of VSMCs by activating ErbB receptors, and therefore we hypothesized that there might be a cross talk between the anti-apoptotic effect of Ang II and the anti-proliferative effect of NRG-1 in VSMCs. The aim of the present study was to observe the expression and role of NRG-1 underlying the inhibitory effect of Ang II on apoptosis of mouse aortic smooth muscle cells (MASMCs). It was found that NRG-1 expression was down-regulated via the circNRG-1/miR-193b-5p-mediated post-transcriptional mechanism in response to Ang II. In addition, NRG-1 overexpression reversed the inhibitory effect of Ang II on apoptosis in MASMCs. Our data may provide a molecular basis for further understanding the mechanism of Ang II in suppressing the apoptosis of MASMCs by decreasing NRG-1 expression at circular RNA and micro RNA levels. The circNRG-1/miR-193b-5p/NRG-1 axis may prove to be a potential target for Ang II to inhibit the apoptosis of VSMCs and lead to vascular remodeling.

• Akt
• Nitric oxide
• PI3K
• PKG
• hydrogen peroxide

• Apoptosis/drug effects
• Apoptosis/genetics
• Blotting, Western
• Caspase 3/genetics
• Caspase 3/metabolism
• Cell Line, Tumor
• Cell Survival/drug effects
• Cell Survival/genetics
• DNA Fragmentation/drug effects
• Humans
• Hydrogen Peroxide/pharmacology
• Immunoprecipitation
• Models, Biological
• Neuroblastoma/genetics
• Neuroblastoma/metabolism
• Nitric Oxide/metabolism
• Signal Transduction/drug effects
• Signal Transduction/genetics

• cGMP
• cardiovascular hemostasis
• gene-targeting
• hypertension
• natriuretic peptide receptor
• receptor signaling

• Arterial remodeling
• Collagen
• Endothelial dysfunction
• Hypertension
• Mathematical model
• Nitric oxide
• Rat carotid

Nitric oxide (NO), which is continuously released from the normal healthy endodermis cell layer of the vascular system, plays a crucial role in the stability and health maintenance of blood vessels.

The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to cyclic mechanical stretch (CMS), which evokes VSMC proliferation, cell death, phenotypic switching, and migration, leading to vascular remodeling. These responses have been observed in many cardiovascular diseases; however, the underlying mechanisms remain unclear. We have revealed that CMS of rat aortic smooth muscle cells (RASMCs) causes JNK- and p38-dependent cell death and that a calcium channel blocker and angiotensin II receptor antagonist decreased the phosphorylation of JNK and p38 and subsequently decreased cell death by CMS. In the present study, we showed that the expression of Cxcl1 and Cx3cl1 was induced by CMS in a JNK-dependent manner. The expression of Cxcl1 was also induced in VSMCs by hypertension produced by abdominal aortic constriction (AAC). In addition, antagonists against the receptors for CXCL1 and CX3CL1 increased cell death, indicating that CXCL1 and CX3CL1 protect RASMCs from CMS-induced cell death. We also revealed that STAT1 is activated in RASMCs subjected to CMS. Taken together, these results indicate that CMS of VSMCs induces inflammation-related gene expression, including that of CXCL1 and CX3CL1, which may play important roles in the stress response against CMS caused by hypertension.

Arginase and nitric oxide synthase (NOS) share a common substrate, l‐arginine, and have opposing effects on vascular remodeling. Arginase is the first step in polyamine and proline synthesis necessary for cellular proliferation, while NO produced from NOS promotes apoptosis. Previously, we identified a single nucleotide polymorphism (SNP) in the arginase‐1 (ARG1) gene, rs2781666 (T‐allele) that was associated with a decreased risk for developing pulmonary hypertension (PH) in a cohort of infants with bronchopulmonary dysplasia (BPD). In this study, we utilized lymphocytes from neonates (the only readily available cells from these patients expressing the two genotypes of interest) with either the rs2781666 SNP (TT) or wild type (GG) to test the hypothesis that the protection of the ARG1 SNP against the development of PH in BPD would involve augmented NO production leading to more apoptosis. Lymphocytes were stimulated with IL‐4, IL‐13, and phorbol myristate acetate (PMA). We found that TT lymphocytes had similar levels of arginase I and arginase II expression, but there was a tendency for lower urea production (a surrogate marker of arginase activity), than in the GG lymphocytes. The TT lymphocytes also had significantly greater NO production than did GG lymphocytes despite no differences in iNOS expression between genotypes. Furthermore, the TT lymphocytes had lower numbers of viable cells, and higher levels of cleaved caspase‐3 than did GG lymphocytes. Inhibiting NOS activity using N_ω‐Nitro‐l‐arginine methyl ester hydrochloride (l‐NAME) significantly decreased cleaved caspase‐3 levels in the TT lymphocytes. These data demonstrate that the TT genotype results in greater levels of NO production leading to more apoptosis, which is consistent with the concept that BPD patients with the TT genotype are protected against the development of PH by producing greater basal levels of endogenous NO.

• Bronchopulmonary dysplasia
• neonate
• oxygen
• preterm
• urea cycle

• Administration, Oral
• Adolescent
• Adult
• Cyclophosphamide/administration & dosage
• Cyclophosphamide/adverse effects
• Enalapril/administration & dosage
• Humans
• Hypertension, Pulmonary/diagnostic imaging
• Hypertension, Pulmonary/drug therapy
• Injections, Intravenous
• Lupus Erythematosus, Systemic/complications
• Middle Aged
• Pulse Therapy, Drug
• Treatment Outcome
• Ultrasonography

• Administration, Oral
• Animals
• Antilymphocyte Serum/immunology
• Antilymphocyte Serum/pharmacology
• Apoptosis/drug effects
• Caspase 3
• Caspases/metabolism
• Dexamethasone/administration & dosage
• Dexamethasone/pharmacology
• Drug Therapy, Combination
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/enzymology
• Endothelium, Vascular/pathology
• Female
• Immunoenzyme Techniques
• In Situ Nick-End Labeling
• Injections, Intraperitoneal
• Mesenteric Arteries/drug effects
• Mesenteric Arteries/metabolism
• Mesenteric Arteries/pathology
• Muscle, Smooth, Vascular/drug effects
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology
• Neutrophils/drug effects
• Neutrophils/immunology
• Neutrophils/pathology
• Nitric Oxide Synthase/metabolism
• Nitric Oxide Synthase Type II
• Oxidative Stress/drug effects
• Peroxynitrous Acid/metabolism
• Phosphodiesterase Inhibitors/administration & dosage
• Phosphodiesterase Inhibitors/toxicity
• Rats
• Rats, Wistar
• Tyrosine/analogs & derivatives
• Tyrosine/metabolism
• Vasculitis/chemically induced
• Vasculitis/metabolism
• Vasculitis/pathology

Nitric oxide (^•NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O₂^•−) regulates cellular proliferation, and ^•NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that ^•NO differentially regulates SOD-1 based on sex.

Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O₂^•− levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±^•NO treatment and SOD-1 protein levels were examined by Western blot.

In vitro, male VSMC have higher O₂^•− levels and lower SOD − 1 activity at baseline compared to female VSMC (P < 0.05). ^•NO decreased O₂^•− levels and increased SOD − 1 activity in male (P<0.05) but not female VSMC. ^•NO also increased sod− 1 gene expression and SOD − 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but ^•NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females.

Our results provide evidence that regulation of the redox environment at baseline and following exposure to ^•NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which ^•NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents.

•

The baseline redox environment in the vascular is sex-dependent.

• Neointimal hyperplasia
• Nitric oxide
• Sex differences
• Superoxide
• Vascular

• Angiotensin II/metabolism
• Animals
• Aorta/drug effects
• Aorta/metabolism
• Aorta/pathology
• Apoptosis/drug effects
• Blood Pressure
• Buthionine Sulfoximine/administration & dosage
• Glutathione/antagonists & inhibitors
• Glutathione/metabolism
• Humans
• Muscle, Smooth, Vascular/drug effects
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology
• Oxidative Stress
• Rats
• Superoxides/metabolism
• Vascular Remodeling/genetics

Thus far, three related natriuretic peptides (NPs) and three distinct sub-types of cognate NP receptors have been identified and characterized based on the specific ligand binding affinities, guanylyl cyclase activity, and generation of intracellular cGMP. Atrial and brain natriuretic peptides (ANP and BNP) specifically bind and activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), and C-type natriuretic peptide (CNP) shows specificity to activate guanylyl cyclase/natriuretic peptide receptor-B (GC-B/NPRB). All three NPs bind to natriuretic peptide receptor-C (NPRC), which is also known as clearance or silent receptor. The NPRA is considered the principal biologically active receptor of NP family; however, the molecular signaling mechanisms of NP receptors are not well understood. The activation of NPRA and NPRB produces the intracellular second messenger cGMP, which serves as the major signaling molecule of all three NPs. The activation of NPRB in response to CNP also produces the intracellular cGMP; however, at lower magnitude than that of NPRA, which is activated by ANP and BNP. In addition to enhanced accumulation of intracellular cGMP in response to all three NPs, the levels of cAMP, Ca²⁺ and inositol triphosphate (IP₃) have also been reported to be altered in different cells and tissue types. Interestingly, ANP has been found to lower the concentrations of cAMP, Ca²⁺, and IP₃; however, NPRC has been proposed to increase the levels of these metabolic signaling molecules. The mechanistic studies of decreased and/or increased levels of cAMP, Ca²⁺, and IP₃ in response to NPs and their receptors have not yet been clearly established. This review focuses on the signaling mechanisms of ANP/NPRA and their biological effects involving an increased level of intracellular accumulation of cGMP and a decreased level of cAMP, Ca²⁺, and IP₃ in different cells and tissue systems.

• Ca2+
• cAMP
• cGMP
• inositol triphosphate
• membrane guanylyl cyclases
• natriuretic peptide receptors
• natriuretic peptides

The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors.

• Adult neurogenesis
• MAPKs
• Nitric oxide
• Subgranular zone
• Subventricular zone
• cell signalling, cGMP
• hippocampus
• neural precursor cell

• Animals
• Arginine/pharmacology
• Carotid Artery Injuries/drug therapy
• Carotid Artery Injuries/etiology
• Carotid Artery Injuries/pathology
• Carotid Artery Injuries/physiopathology
• Electric Stimulation/adverse effects
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Isosorbide Dinitrate/analogs & derivatives
• Isosorbide Dinitrate/pharmacology
• Isosorbide Dinitrate/therapeutic use
• Mice

• nanotechnology
• intravascular gas delivery
• cardiovascular
• hypertension
• vasodilation

• Animals
• Cricetinae
• Delayed-Action Preparations
• Drug Delivery Systems
• Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry
• Hydrogen-Ion Concentration
• Male
• Nanoparticles/chemistry
• Nanotechnology/instrumentation
• Nanotechnology/methods
• Nitric Oxide/administration & dosage
• Nitric Oxide/chemistry
• Nitric Oxide/metabolism
• Nitric Oxide/pharmacokinetics
• Particle Size
• Signal Transduction

• P01 HL071064 NHLBI NIH HHS
• P01 HL071064-05 NHLBI NIH HHS

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Apoptosis
• BRCA2 Protein/genetics
• Blotting, Western
• Carotid Arteries/metabolism
• Carotid Arteries/pathology
• Carotid Arteries/surgery
• Catalase/metabolism
• Cell Proliferation
• DNA Damage
• DNA Glycosylases/genetics
• DNA Repair/genetics
• DNA-Binding Proteins/genetics
• Deoxyguanosine/analogs & derivatives
• Deoxyguanosine/metabolism
• Disease Models, Animal
• Gene Expression
• Histones/antagonists & inhibitors
• Histones/metabolism
• Immunohistochemistry
• Male
• Phosphoproteins/antagonists & inhibitors
• Phosphoproteins/metabolism
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Tumor Suppressor Protein p53/metabolism
• Vascular System Injuries/genetics
• Vascular System Injuries/metabolism

• nitric oxide
• cgmp
• pkg
• phosphorylation
• smooth muscle
• gene expression
• phenotype
• ubiquitin

• Animals
• COS Cells
• Cattle
• Chlorocebus aethiops
• Cyclic GMP/analogs & derivatives
• Cyclic GMP/pharmacology
• Cyclic GMP-Dependent Protein Kinase Type I
• Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors
• Cyclic GMP-Dependent Protein Kinases/metabolism
• Down-Regulation/drug effects
• Humans
• Isoenzymes/metabolism
• Mice
• Models, Biological
• Muscle, Smooth, Vascular/cytology
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/enzymology
• Nitric Oxide/pharmacology
• Phosphodiesterase Inhibitors/pharmacology
• Phosphorylation/drug effects
• Phosphoserine/metabolism
• Rats
• Rats, Sprague-Dawley
• Transfection
• Ubiquitination/drug effects

• R01 HL066164-08 NHLBI NIH HHS
• HL 66164 NHLBI NIH HHS
• DK 40029 NIDDK NIH HHS
• R01 HL066164 NHLBI NIH HHS
• R01 DK040029 NIDDK NIH HHS

• cgmp
• cardiovascular disease
• soluble guanylyl cyclase
• natriuretic peptide receptor
• pkg
• phosphodiesterases

• Animals
• Cardiovascular Agents/pharmacology
• Cardiovascular Agents/therapeutic use
• Cardiovascular Diseases/physiopathology
• Cardiovascular Diseases/therapy
• Cardiovascular Physiological Phenomena/drug effects
• Cyclic GMP/physiology
• Humans
• Signal Transduction/drug effects
• Signal Transduction/physiology

• R01 HL089297-01A1 NHLBI NIH HHS
• T32 HL007227 NHLBI NIH HHS
• R01 HL089297-02 NHLBI NIH HHS
• T32 HL007227-33 NHLBI NIH HHS
• R01 HL089297 NHLBI NIH HHS

β-Arrestins, originally discovered as terminators of G protein-coupled receptor signaling, have more recently been appreciated to also function as signal transducers in their own right, although the consequences for cellular physiology have not been well understood. Here we demonstrate that β-arrestin-2 mediates anti-apoptotic cytoprotective signaling stimulated by a typical 7-transmembrane receptor the angiotensin ATII 1A receptor, expressed endogenously in rat vascular smooth muscle cells or by transfection in HEK-293 cells. Receptor stimulation leads to concerted activation of two pathways, ERK/p90RSK and PI3K/AKT, which converge to phosphorylate and inactivate the pro-apoptotic protein BAD. Anti-apoptotic effects as well as pathway activities can be stimulated by an angiotensin analog (SII), which has been previously shown to activate β-arrestin but not G protein-dependent signaling, and are abrogated by β-arrestin-2 small interfering RNA. These findings establish a key role for β-arrestin-2 in mediating cellular cytoprotective functions by a 7-transmembrane receptor and define the biochemical pathways involved.

Initially recognized as a physiologic regulator of blood pressure and body fluid homeostasis, angiotensin (Ang) II has now been shown in innumerable experiments and clinical studies to contribute to the development and maintenance of cardiovascular disease. Dissection of its signaling mechanisms over the past decades has led to the discovery of several novel concepts, such as tissue-specific metabolism of Ang peptides. Identification and cloning of the various receptors through which Ang II acts on almost all tissues has led to the development of specific pharmacologic inhibitors with proven clinical benefit in patients with cardiovascular disorders. Work on the G-protein-coupled Ang II Type 1 receptor has demonstrated that different receptors interact through oligomerization, compartmentalization, and transactivation, and may explain how Ang II can activate G-protein-independent pathways. Unraveling the downstream effects of Ang II in specific cell types corroborates the importance of the cellular redox state on certain signaling pathways. Finally, the effects of Ang II on cell function and phenotype, such as the expression of inflammatory cytokines and receptors promoting the recruitment of inflammatory cells into vascular tissues, have indicated its role in local inflammation as a general pathogenetic basis of cardiovascular disease. The recognition of Ang II as a contributor to such fundamental pathophysiologic mechanisms, which are believed to be a common pathway for diverse cardiovascular risk factors like hypertension and diabetes, has greatly advanced our knowledge of pathologic signaling in vascular tissues and may help to eventually define novel targets for pharmacologic interventions.