Medial Hypertrophy Research Articles

Arterialization of Central Pulmonary Vein

, Online Figs. 3 to 5, Online Video 1) revealed uniform nar-rowing of the central vein with severe ostial stenosis. Central pulmonary-vein obstruction isknown to trigger progressive medial hypertrophy and intimal fibrosis of the affected venoustree (1). Gradually, venous pressure and waveform arterialize. Currently, we do not know thelong-term clinical implications of venous arterialization due to pulmonary vein ablation. Regu-lar monitoring was advised for this asymptomatic patient.

Incidence of Complex Vascular Lesions (Plexiform‐Like Lesions) in the Lungs of 1 to 21‐Day‐Old Domestic Fowl

Plexogenic arteriopathy rarely develops in existing animal models of pulmonary arterial hypertension (PAH). Rapidly growing chickens spontaneously develop PAH accompanied by the formation of plexiform‐like complex vascular lesions (CVL). The objective of this study was to evaluate the frequency with which at least one CVL per tissue section was observed in the lungs of chicks from lines selected for susceptibility (S) or resistance (R) to PAH. At 1, 7, 14 and 21 days of age (n ≥ 10 chicks per age and line) the CVL incidences were 33, 30, 35 and 50% for S chicks, and 20, 30, 28, and 25% for R chicks. The combined CVL incidences over days 1–21 did not differ significantly (P = 0.105) between S (36.4%) and R (25.5%) chicks. Early CVL formed when proliferating intimal cells occluded an arteriole lumen distal to branch points in muscular inter‐parabronchial arterioles that typically exhibited medial hypertrophy and intimal proliferation. Mature CVL in chicken lungs strikingly resemble published photomicrographs of plexiform lesions in the lungs of human PAH patients. The development of CVL in the lungs of young chicks suggests a complex interaction between pulmonary hemodynamics, vascular development and vascular pathology. Supported by NIH grant 1R15HL092517.

Expression of Angioproliferative Molecules in Plexiform like Lesions in Lungs of Domestic Fowl Selected for Susceptibility to Pulmonary Arterial Hypertension

Domestic fowl (broiler chickens) bred for meat production spontaneously develop pulmonary arterial hypertension (PAH) accompanied by the formation of plexiform‐like complex vascular lesions (CVLs). CVLs formed distal to branch points in inter‐parabronchial pulmonary arterioles that typically exhibit medial hypertrophy and intimal proliferation. The CVLs in the lungs of broilers closely resemble the histology of plexiform lesions in the lungs of human PAH patients. Paraformaldehyde fixed lung tissues from 8‐ to 24‐week old broilers were stained immunohistochemically for detection of various angioproliferative molecules expressed in the CVLs. These molecules include: smooth muscle actin; von Willebrand factor; vascular endothelial growth factor (VEGF); VEGF receptor II; hypoxia inducible factor 1 alpha; survivin; collagen; fibronectin; and tenascin. The CVLs in broiler lungs exhibited positive staining for these molecules. Expression of these molecules within the CVL of PAH‐susceptible broilers combined with the close histological resemblance of CVLs to plexiform lesions of human PAH patients further supports the use of broilers from our PAH susceptible line as an excellent animal model for PAH and plexogenic arteriopathy.“Supported by NIH grant 1R15HL092517”

Overexpression of endothelin-1 and endothelin receptors in the pulmonary arteries of failed Fontan patients

BackgroundEndothelin-1 (ET-1), a potent vasoconstrictor, is considered to be implicated in failing Fontan circulation, however the expressions of ET-1 and endothelin receptor type A (ETAR) and type B (ETBR) in the pulmonary arteries of failed Fontan patients were not elucidated. MethodsImmunohistochemistry and quantitative real-time PCR were used to analyse the expression levels of ET-1 and its receptors in the pulmonary arteries of the autopsy lung tissues of the patients who died after the Fontan procedure (n=10). We divided these patients into 3 groups, failed Fontan (n=4), heart failure (n=3) and non-failed Fontan (n=3), and then compared those to the age-matched normal controls (n=4). ResultsThe intra-acinar pulmonary arteries of failed Fontan patients showed significant medial hypertrophy. Computational optical density analyses of the immunostaining revealed that the expressions of ET-1, ETAR, and ETBR in the intra-acinar pulmonary arteries were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls), however no significant difference was observed between the non-failed Fontan patients and the normal controls. Quantitative real-time PCR analyses confirmed that the mRNA expressions of ET-1, ETAR, and ETBR were significantly increased in the failed Fontan patients (P<0.05 vs. normal controls). ConclusionThe overexpression of ET-1 and its receptors in the pulmonary arteries can cause pulmonary vasoconstriction and vascular remodelling, leading to failed Fontan circulation. This study suggests a histopathological rationale for the potential benefits of endothelin receptor antagonists in patients with failing Fontan circulation.

Moving beyond the “Allegory of the Cave” in the assessment of pulmonary arterial hypertension

PULMONARY ARTERIAL HYPERTENSION (PAH) remains a clinically vexing problem considering the high morbidity and mortality that plagues this entity despite indication of improved survival after the introduction of more targeted therapy. While this syndrome is well described from a pathological standpoint the mechanisms involved in the pulmonary vascular remodeling are less clear but are thought to involve endothelial dysfunction and proliferation of various cell types that comprise the wall of distal pulmonary vessels (3). The specific mechanisms leading to distal vessel obliteration and increased pulmonary vascular resistance have been particularly elusive for several decades (14), and although vasoconstriction as a primary event was the focus of research and targeted therapy in early studies, the PAH research community has witnessed a paradigm shift in recent years with a strong tendency to now view the PAH lesion as a quasi-cancerous process (12). In this issue of the Journal of Applied Physiology, Schwenke et al. (8) bring a new tool for assessment of the distal pulmonary vasculature and shake an old specter, vasoconstriction. The investigators employ synchrotron radiation microangiography (SRA), a fairly novel and powerful technique, to more directly evaluate vascular tone in a classic animal model of PAH, monocrotaline (MCT)-challenged rats, providing new insight into regional specific responses of the pulmonary circulation in PAH. SRA allows for both the measurement and assessment of control of blood flow in vivo and collection of data on small arteries and arterioles in situ over time (10). Thus it can supply superior information on kinetic events relative to ex vivo techniques. Since SRA has no focal plane, it can visualize both surface and penetrating vessels simultaneously unlike intravital microscopy, which is limited to assessment of vessel caliber at a single vascular plan. In dynamic organs such as the lung and heart, which are subject to motion, temporal

Aspirin Attenuates Pulmonary Arterial Hypertension in Rats by Reducing Plasma 5-Hydroxytryptamine Levels

Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary pressure, right ventricular failure, and death. The typical pathological changes include medial hypertrophy, intimal fibrosis and in situ thrombosis. Serotonin (5-HT) and other factors contribute to the development of pathologic lesions. Aspirin (ASA), a platelet aggregation inhibitor, inhibits 5-HT release from platelets. The aim of this study was to determine the efficacy of ASA in preventing or attenuating PAH. Sprague-Dawley rats injected with monocrotaline (MCT) developed severe PAH within 31days. One hundred forty rats were randomized to receive either vehicle or ASA (0.5, 1, 2, or 4mg/kg/day). The pre-ASA group was treated with ASA (1mg/kg/day) for 30days before the MCT injection. Thirty-one days after the injection (day 61 for the pre-ASA group), pulmonary arterial pressure (PAP), right ventricular hypertrophy and pulmonary arteriole thickness were measured. Plasma 5-HT was measured by high-performance liquid chromatography. Aspirin suppressed PAH and increased the survival rate compared with the control group (84 vs. 60%, P<0.05). Aspirin treatment also reduced right ventricular hypertrophy and pulmonary arteriole proliferation in ASA-treated PAH model. In addition, plasma 5-HT was decreased in our ASA-treated PAH model. The degree of 5-HT reduction was associated with systolic PAP, right ventricular hypertrophy and wall thickness of pulmonary arterioles in rats. These results showed that ASA treatment effectively attenuated MCT-induced pulmonary hypertension, right ventricular hypertrophy, and occlusion of the pulmonary arteries. The effects of ASA was associated with a reduction of 5-HT.

Mechanisms of Prevention of Pulmonary Hypertension-Induced Right-Ventricular Failure by Intralipid

Intralipid (ILP) has been used for treatment of local anesthetic-induced cardiac-arrest and as source of parenteral nutrition. Some of its constituents are precursors of pulmonary vasodilator prostaglandins. Pulmonary hypertension (PH) is associated with pulmonary vascular remodeling leading to right-ventricular (RV) hypertrophy and failure. Recently we found that ILP prevents PH in rats. Here we investigated the mechanisms involved in this prevention. Rats were treated with monocrotaline(60 mg/kg) to induce PH, and then either received daily ILP (1 mL of 20% ILP/day) for 30days or left untreated to develop RV failure (RVF). Saline treated rats served as control. Serial echocardiography was performed to monitor cardiopulmonary hemodynamics., RV pressure (RVP) was recorded by direct cardiac catheterization right before sacrifice. Immunohistochemistry, confocal-microscopy, Western Blot analysis and RT-PCR were performed. RVF group developed PH that led to RVF later with significantly increased RVP (70±5mmHg,n=10) and depressed RV ejection fraction (RVEF=34±2%). Severe structural changes in RV and lung were observed in RVF group including RV-hypertrophy, increased lung weight, pulmonary medial hypertrophy, fibrosis, apoptosis (upregulation of Caspase-3 (∼10fold)), inflammation (increased expression of IL-6) and suppression of angiogenesis (decreased VEGF and capillary-density). Furthermore, RVF was associated with downregulation of phospho-eNOS(∼4fold), Caveolin-1(∼6fold) adenosine-A2B receptor and estrogen receptor-β in lungs. In the RV, adenosine-A2A receptor and estrogen receptor-b were downregulated in RVF. ILP therapy prevented PH-induced RVF by restoring RVP(30±2mmHg,n=8) and RVEF(63±1.5%) and attenuating RV hypertrophy and lung remodeling. ILP suppressed inflammation and fibrosis along-with improving angiogenesis and restoring phospho-eNOS, Caveolin-1 in lungs and Caspase-3, adenosine-A2 and estrogen receptor-β expression in lungs and RV. In conclusion ILP prevented PH and RV-failure by preserving cardiopulmonary structure and function and enhancing perfusion via adenosine receptor, estrogen receptor-b and eNOS-mediated mechanisms.

Idiopathic pulmonary arterial hypertension: An avian model for plexogenic arteriopathy and serotonergic vasoconstriction

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance attributable to vasoconstriction and vascular remodeling of small pulmonary arteries. Vascular remodeling includes hypertrophy and hyperplasia of smooth muscle (medial hypertrophy) accompanied in up to 80% of the cases by the formation of occlusive plexiform lesions (plexogenic arteriopathy). Patients tend to be unresponsive to vasodilator therapy and have a poor prognosis for survival when plexogenic arteriopathy progressively obstructs their pulmonary arteries. Research is needed to understand and treat plexogenic arteriopathy, but advances have been hindered by the absence of spontaneously developing lesions in existing laboratory animal models. Young domestic fowl bred for meat production (broiler chickens, broilers) spontaneously develop IPAH accompanied by semi-occlusive endothelial proliferation that progresses into fully developed plexiform lesions. Plexiform lesions develop in both female and male broilers, and lesion incidences (lung sections with lesions/lung sections examined) averaged approximately 40% in 8 to 52 week old birds. Plexiform lesions formed distal to branch points in muscular interparabronchial pulmonary arteries, and were associated with perivascular mononuclear cell infiltrates. Serotonin (5-hydroxytryptamine, 5-HT) is a potent vasoconstrictor and mitogen known to stimulate vascular endothelial and smooth muscle cell proliferation. Serotonin has been directly linked to the pathogenesis of IPAH in humans, including IPAH linked to serotonergic anorexigens that trigger the formation of plexiform lesions indistinguishable from those observed in primary IPAH triggered by other causes. Serotonin also plays a major role in the susceptibility of broilers to IPAH. This avian model of spontaneous IPAH constitutes a new animal model for biomedical research focused on the pathogenesis of IPAH and plexogenic arteriopathy.

Progenitor cells in pulmonary vascular remodeling.

Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow–derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow–derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure.

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Pulmonary arterial hypertension (PAH) is a progressive fatal disease 1, 2. All forms of chronic pulmonary hypertension are characterised by cellular and structural changes in the walls of the pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are common 3. Virtually all of these changes are characterised, to a greater or lesser degree, by increased numbers of cells expressing smooth muscle α-actin (α-SMA), as well as the accumulation of inflammatory cells 4–7. At present, neither the origin of the accumulating cells, particularly those expressing α-SMA, nor the molecular mechanisms operating to cause their accumulation has been fully delineated. Traditionally, it has been thought that the α-SMA-expressing and/or collagen-producing cells accumulating in vascular lesions were exclusively derived from resident vascular cells. However, since the late 1990s, this concept has been extended by the fact that bone-marrow-derived circulating progenitor cells are recruited to sites of vascular injury and contribute to both the vascular repair and pathological remodelling by differentiating into cells expressing mesenchymal or even smooth-muscle-like characteristics 8–10. Among the many populations of progenitor cells that may be recruited to the vessel wall and assume mesenchymal cell characteristics are fibrocytes. These cells were initially described by Bucala et al. 11 as circulating bone-marrow-derived cells with the ability to adapt a mesenchymal phenotype. They share certain features with both fibroblasts and monocytes, and this combination of connective tissue cell and myeloid cell characteristics permits their identification by a number of markers. Fibrocytes express the stem cell marker CD34, the pan-haematopoietic marker CD45 and monocyte markers, such as CD14 and CD11, and produce components of the connective tissue matrix, including collagen I, collagen III and vimentin 12, 13. Fibrocytes display many properties that are important for wound …

Sex Hormones and Vascular Protection in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a serious disease and a major public health problem with approximately 1000 new patients diagnosed every year in the United States.1, 2 PAH is a progressive disease involving impaired pulmonary vascular structure and function and is ultimately lethal due to right ventricular failure. Recent insights into the pathogenesis of PAH have lead to more promising therapeutic approaches and improved outcomes; however, the mortality rates associated with PAH remain unacceptably high.1, 3, 4

CT Findings in Diseases Associated with Pulmonary Hypertension: A Current Review

Pulmonary hypertension may primarily affect either the arterial (precapillary) or the venous (postcapillary) pulmonary circulation. Pulmonary arterial hypertension may be idiopathic or arise in association with chronic pulmonary thromboembolism; pulmonary embolism caused by tumor cells, parasitic material, or foreign material; parenchymal lung disease; liver disease; vasculitis; human immunodeficiency virus infection; or a left-to-right cardiac shunt. Its histologic characteristics include vascular changes-medial hypertrophy, intimal cellular proliferation, intraluminal thrombosis, and the development of plexiform lesions-that manifest primarily in the muscular pulmonary arteries. Features of pulmonary arterial hypertension that may be seen at computed tomography (CT) are central pulmonary artery dilatation, abrupt narrowing or tapering of peripheral pulmonary vessels, right ventricular hypertrophy, right ventricular and atrial enlargement, dilated bronchial arteries, and a mosaic pattern of attenuation due to variable lung perfusion. Pulmonary venous hypertension may result from pulmonary veno-occlusive disease, pulmonary venous compression by extrinsic lesions (eg, mediastinal fibrosis), left-sided cardiac disease, or pulmonary vein stenosis. Its histologic hallmarks include venous intimal cellular proliferation, medial hypertrophy, and thickening of the internal elastic lamina; capillary congestion and proliferation; interlobular septal thickening; lymphatic dilatation; and, sometimes, venous infarction and vascular changes characteristic of pulmonary arterial hypertension. CT scans in patients with pulmonary venous hypertension show pulmonary interstitial and alveolar edema with signs of pulmonary arterial hypertension. High-resolution CT with standard axial and angiographic acquisitions is useful for identifying underlying disorders and differentiating among the various causes of secondary pulmonary hypertension.

Spontaneous Pneumothorax in a Dog Secondary toDirofilaria ImmitisInfection

A 5-year-old female spayed Labrador Retriever dog was referred to the Louisiana State University Veterinary Teaching Hospital for treatment of pneumothorax. Thoracic radiographs and computed tomography showed spontaneous pneumothorax, thoracic lymphadenopathy, pulmonary hypertension, and multifocal pulmonary bulla lesions. At surgery, numerous adult nematodes protruded from the parenchyma of the left caudal and accessory lung lobes and pulmonary arteries. On histopathology, multiple adult filarid nematodes were observed within the pulmonary blood vessels. Broad foci of necrosis of the pulmonary parenchyma were present. The tunica intima of the pulmonary arteries was markedly thickened by intimal fibrosis and medial hypertrophy. The final diagnosis was severe Dirofilaria immitis infection that resulted in pulmonary vascular lesions and focally extensive infarcts of the pulmonary parenchyma with bulla formation and rupture causing spontaneous pneumothorax. The dog received antibiotic and steroid therapy, as well as adulticide treatment, and recovered.

Increase in GLUT1 in Smooth Muscle Alters Vascular Contractility and Increases Inflammation in Response to Vascular Injury

The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003). In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-β activity.

Does atorvastatin induce aortic smooth muscle cell apoptosis in vivo?

It has been reported that HMG-CoA reductase inhibitors such as atorvastatin induce vascular smooth muscle cell (SMC) apoptosis in vitro. However, this effect remains to be demonstrated in vivo. The present studies were designed to test the ability of atorvastatin to induce SMC apoptosis in vivo, using the spontaneously hypertensive rat (SHR) as a well-known reference model of SMC apoptosis induction in vivo by cardiovascular drugs including the calcium channel blocker amlodipine. Atorvastatin was administered to SHR for 3 or 6weeks either alone or together with amlodipine, a drug combination clinically available to patients. Primary endpoints included aortic medial hypertrophy and aortic SMC hyperplasia, internucleosomal DNA fragmentation and expression of the apoptosis regulatory proteins Bax and Bcl-2. The SHR aorta showed no evidence of SMC apoptosis induction by atorvastatin, even at the high dose of 50mgkg−1day−1, although the statin significantly reduced oxidative stress after 3weeks and blood pressure after 6weeks of administration. Amlodipine-induced regression of aortic hypertophy and aortic SMC hyperplasia were dose- and time-dependent, but there was no interaction between atorvastatin and amlodipine in modulating the primary endpoints. These results do not support the notion that atorvastatin induces SMC apoptosis in the aortic media in vivo.

E0067 Aspirin attenuates pulmonary arterial hypertension in rats by reducing plasma 5hydroxytryptamine level

Pulmonary arterial hypertension (PAH) is characterised by increasing pulmonary pressure, right ventricular failure, and death. The typical pathological changes include medial hypertrophy, intimal fibrosis and in situ thrombosis. 5-HT and...

Chronic hypoxia-induced pulmonary hypertension in rat: the best animal model for studying pulmonary vasoconstriction and vascular medial hypertrophy

Numerous animal models of pulmonary hypertension (PH) are currently used to evaluate new therapies; investigating both their efficacy and the mechanism of their effect. They are also used to explore the biochemical mechanisms at work, with a view of identifying new drug targets. The chronic hypoxia-induced PH rat model is among the most commonly used animal models of PH. It is well known that alveolar hypoxia causes constriction of resistance vessels in the pulmonary vascular bed and followed by medial hypertrophy and muscularization of pulmonary arterioles, leading to sustained elevation in pulmonary artery pressure (PAP). The combination of these physiologic and pathologic processes imposes a mechanical and obliterative impact on the pulmonary circulation which mimics the common clinical features of pulmonary arterial hypertension (PAH) in patients. Researchers have slowly unraveled various etiology components in initiating and modifying influences in the hypoxia-induced PH rat model and the accumulation of knowledge could improve future treatments of PAH. This review examines the strengths and limitations of the chronic hypoxia-induced rat PH model and its value in the assessment of new treatments for PH.

Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets

In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions. Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5). High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05). Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

The etiopathogenesis of pulmonary hypertension: inflammation, vascular remodeling

Pulmonary arterial hypertension (PAH) is a progressive disease marked by increased pulmonary artery resistance leading to right heart failure with a high mortality. PAH is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, inflammation, and thrombosis in situ. Elevated pulmonary vascular resistance is the result of an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Recent evidence demonstrates that inflammatory processes are involved in the generation of pulmonary vascular remodeling leading to PAH. Viral infections or similar immune-modulators trigger auto-antibody generation by endothelial injury and indirectly lead to PAH. All these immune-modulators associated with PAH, are also known to decrease the regulatory subgroups (CD4) of T cells. With a recognition of the important role of inflammation in the development of PAH, anti-inflammatory agents and anti-cancer drugs are accepted as potential specific targets for PAH treatment. Though clinical studies are not enough, anti-inflammatory agents seem to be promising in the treatment of this devastating disease.

Attenuated cardiovascular hypertrophy and oxidant generation in response to angiotensin II infusion in glutaredoxin-1 knockout mice

Glutaredoxin-1 (Glrx) is a thioltransferase that regulates protein S -glutathiolation. To elucidate the role of endogenous Glrx in cardiovascular disease, Glrx knockout (KO) mice were infused with angiotensin II (Ang II) for 6 days. After Ang II infusion, body weight and blood pressure were similar between WT and Glrx KO mice. However, compared to WT mice, Glrx KO mice demonstrated (1) less cardiac and aortic medial hypertrophy, (2) less oxidant generation in aorta as assessed by dihydroethidium staining and nitrotyrosine, (3) decreased phosphorylation of Akt in the heart, and (4) less expression of inducible NOS in aorta and heart. In cultured embryonic fibroblasts from Glrx KO mice, S -glutathiolation of actin was enhanced and actin depolymerization was impaired after hydrogen peroxide stimulation compared with WT cells. Furthermore, oxidant generation in phorbol ester-stimulated fibroblasts and RAW 264.7 macrophage-like cells was lower with Glrx siRNA knockdown. These data indicate that Ang II-induced oxidant production and hypertrophic responses were attenuated in Glrx KO mice, which may result from impaired NADPH oxidase activation.