The novel roles of YULINK in the migration, proliferation and glycolysis of pulmonary arterial smooth muscle cells: implications for pulmonary arterial hypertension.

BACKGROUND: Abnormal remodeling of the pulmonary vasculature, characterized by the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) along with dysregulated glycolysis, is a pathognomonic feature of pulmonary arterial hypertension (PAH). YULINK (MIOS, Entrez Gene: 54468), a newly identified gene, has been recently shown to possess pleiotropic physiologic functions. This study aims to determine novel roles of YULINK in the regulation of PAH-related pathogenesis, including PASMC migration, proliferation and glycolysis. RESULTS: Our results utilized two PAH-related cell models: PASMCs treated with platelet-derived growth factor (PDGF) and PASMCs harvested from monocrotaline (MCT)-induced PAH rats (PAH-PASMCs). YULINK modulation, either by knockdown or overexpression, was found to influence PASMC migration and proliferation in both models. Additionally, YULINK was implicated in glycolytic processes, impacting glucose uptake, glucose transporter 1 (GLUT1) expression, hexokinase II (HK-2) expression, and pyruvate production in PASMCs. Notably, YULINK and GLUT1 were observed to colocalize on PASMC membranes under PAH-related pathogenic conditions. Indeed, increased YULINK expression was also detected in the pulmonary artery of human PAH specimen. Furthermore, YULINK inhibition led to the suppression of platelet-derived growth factor receptor (PDGFR) and the phosphorylation of focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), and protein kinase B (AKT) in both cell models. These findings suggest that the effects of YULINK are potentially mediated through the PI3K-AKT signaling pathway. CONCLUSIONS: Our findings indicate that YULINK appears to play a crucial role in the migration, proliferation, and glycolysis in PASMCs and therefore positioning it as a novel promising therapeutic target for PAH.

Technical Aspects and Common Pitfalls of Norwood With Modified Blalock Taussig Shunt.

The Stage 1 Norwood procedure is the first of 3 stages in the surgical palliation of hypoplastic left heart syndrome and certain other single ventricle lesions with systemic outflow obstruction. In this article, we address some technical aspects and common pitfalls of the Norwood procedure with systemic to pulmonary shunt for HLHS palliation. We report our results with the Norwood with Blalock Taussig shunt in a cohort of 44 patients over a 7-year period in 2 institutions in Argentina. The results of the Norwood procedure have improved significantly through the understanding and refinement of the surgical techniques. Procedures must be technically perfect since residual lesions are poorly tolerated. Norwood with a modified Blalock Taussig shunt can be performed with low mortality and may provide excellent long-term outcomes.

AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension (HPH) is characterized by sustained elevation of pulmonary artery pressure produced by vasoconstriction and hyperproliferative remodeling of the pulmonary artery and subsequent right ventricular hypertrophy (RVH). The search for therapeutic targets for cardiovascular pathophysiology has extended in many directions. However, studies focused on mitigating high-altitude pulmonary hypertension (HAPH) have been rare. Because AMP-activated protein kinase (AMPK) is involved in cardiovascular and metabolic pathology, AMPK is often studied as a potential therapeutic target. AMPK is best characterized as a sensor of cellular energy that can also restore cellular metabolic homeostasis. However, AMPK has been implicated in other pathways with vasculoprotective effects. Notably, cellular metabolic stress increases the intracellular ADP/ATP or AMP/ATP ratio, and AMPK activation restores ATP levels by activating energy-producing catabolic pathways and inhibiting energy-consuming anabolic pathways, such as cell growth and proliferation pathways, promoting cardiovascular protection. Thus, AMPK activation plays an important role in antiproliferative, antihypertrophic and antioxidant pathways in the pulmonary artery in HPH. However, AMPK plays contradictory roles in promoting HPH development. This review describes the main findings related to AMPK participation in HPH and its potential as a therapeutic target. It also extrapolates known AMPK functions to discuss the less-studied HAPH context.

Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-γ Expression in Pulmonary Artery.

Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator-activated receptor (PPAR-γ) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-γ expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-γ in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity.

Anti-Inflammatory Effect of Allicin Associated with Fibrosis in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, TNF-α, NFκB p65, Iκß, TGF-ß, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-ß were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1ß, and Cd68 in the lung. In addition, TGF-ß, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-ß. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.

Shear stress-exposed pulmonary artery endothelial cells fail to upregulate HSP70 in chronic thromboembolic pulmonary hypertension.

The pathophysiological mechanisms underlying chronic thromboembolic pulmonary hypertension (CTEPH) are still unclear. Endothelial cell (EC) remodeling is believed to contribute to this pulmonary disease triggered by thrombus and hemodynamic forces disbalance. Recently, we showed that HSP70 levels decrease by proatherogenic shear stress. Molecular chaperones play a major role in proteostasis in neurological, cancer and inflammatory/ infectious diseases. To shed light on microvascular responses in CTEPH, we characterized the expression of molecular chaperones and annexin A2, a component of the fibrinolytic system. There is no animal model that reproduces microvascular changes in CTEPH, and this fact led us to isolated endothelial cells from patients with CTEPH undergoing pulmonary endarterectomy (PEA). We exposed CTEPH-EC and control human pulmonary endothelial cells (HPAEC) to high- (15 dynes/cm2) or low- (5 dynes/cm2) shear stress. After high-magnitude shear stress HPAEC upregulated heat shock protein 70kDa (HSP70) and the HSP ER paralogs 78 and 94kDa glucose-regulated protein (GRP78 and 94), whereas CTEPH-ECs failed to exhibit this response. At static conditions, both HSP70 and HSP90 families in CTEPH-EC are decreased. Importantly, immunohistochemistry analysis showed that HSP70 expression was downregulated in vivo, and annexin A2 was upregulated. Interestingly, wound healing and angiogenesis assays revealed that HSP70 inhibition with VER-155008 further impaired CTEPH-EC migratory responses. These results implicate HSP70 as a novel master regulator of endothelial dysfunction in type 4 PH. Overall, we first show that global failure of HSP upregulation is a hallmark of CTEPH pathogenesis and propose HSP70 as a potential biomarker of this condition.

Caracterización de la fisiología restrictiva del ventrículo derecho mediante flujo 4D / 4-D flow characterization of right ventricular restrictive physiology

Abstract: Right ventricular restrictive physiology (RVRP) occurs in diverse clinical scenarios, most frequently after repair of Tetralogy of Fallot (TOF). Cardiac magnetic resonance (CMR) can comprehensively evaluate RVRP using 4D flow along with anatomical and fibrosis characterization. Also, RVRP is associated with less pulmonary regurgitation and fewer right ventricle enlargement; its long term protective role is debated. RVRP is a challenging and relevant diagnosis, which hallmark is the presence of antegrade pulmonary arterial Flow in late diastole throughout the respiratory cycle. Also, other hemodynamic findings could aid such us flow in; caval veins, suprahepatic, coronary sinus and tricuspid valve. Obtaining all these flow curves is virtually impossible by echocardiography. CMR with 4DF is a unique and powerful technique enabling this comprehensive hemodynamic evaluation as depicted in this case.

Agenesia da artéria pulmonar direita: descrição de caso / Agenesis of the right pulmonary artery: a case report

RESUMO: Agenesia isolada da artéria pulmonar direita ou esquerda é uma rara anomalia congênita dada pela falta do desenvolvimento embriológico de um dos arcos aórticos. A apresentação clínica é variável, sendo a mais comum na infância, na forma de hipertensão pulmonar contralateral. No adulto, a hemoptise pode ser uma das manifestações clínicas, e nos indivíduos assintomáticos esta anomalia pode ser reconhecida em exames de diagnóstico por imagem. Relatamos o caso de paciente do sexo feminino, 63 anos, encaminhada para investigação de imagem nodular no hilo pulmonar esquerdo observada em radiografia torácica. Tomografia computadorizada evidenciou agenesia da artéria pulmonar direita com suprimento arterial pulmonar homolateral ocorrendo por vasos colaterais, pulmão esquerdo com proeminência das artérias e veias hilares e peri-hilares, provavelmente simulando uma nodulação na radiografia realizada previamente, volume discretamente reduzido do pulmão direito com espessamento liso dos septos interlobulares secundário, provavelmente devido ao aumento da microcirculação colateral intraparenquimatosa. (AU)

ABSTRACT: Isolated agenesis of the right or left pulmonary artery is a rare congenital anomaly due to the lack of embryological development of one of the aortic arches. The clinical presentation is variable, being the most common in childhood, in the form of contralateral pulmonary hypertension. In adults, hemoptysis may be one of the clinical manifestations, and in asymptomatic individuals, this anomaly can be recognized in diagnostic imaging tests. We report the case of a female patient, 63 years old, referred for investigation of the nodular image in the left pulmonary hilum observed on chest radiography. Computed tomography showed right pulmonary artery agenesis with homolateral pulmonary arterial supply occurring by collateral vessels, left lung with a prominence of the hilar and peri-hilar arteries and veins probably simulating nodulation on the radiograph previously performed, a discreetly reduced volume of the right lung with smooth thickening of the septa secondary to probably increased intraparenchymal collateral microcirculation. (AU)

Agenesia de artéria pulmonar direita: relato de caso / Agenesis of right pulmonary artery: case report

RESUMO: A agenesia de artéria pulmonar é uma malformação congênita rara, que ocorre devido ao não desenvolvimento do sexto arco aórtico. Entretanto, não é relacionada com malformações cardíacas. Além das artérias intrapulmonares, a vascularização pulmonar e a árvore brônquica geralmente não sofrem alterações. No presente relato, a paciente apresenta quadro de febre, tosse produtiva e taquipneia. Devido à clínica, optou-se por realizar radiografia simples de tórax, na qual se evidenciou a presença de opacidade interstício-alveolar peri-hilar à direita com desvio do mediastino à direita e assimetria da transparência pulmonar. Então, foi solicitada tomografia computadorizada de tórax que evidenciou pulmão direito de volume reduzido. Para melhor compreensão, realizou-se angiotomografia computadorizada do tórax, a qual detectou agenesia da artéria pulmonar direita. Importância do problema: relatar um caso de agenesia de artéria pulmonar direita. (AU)

ABSTRACT: Pulmonary artery agenesis is a rare congenital malformation, which occurs due to the non-development of the sixth aortic arch. However, it is not related to cardiac malformation, and also the intrapulmonary arteries, as well as the pulmonary vascularization and the bronchial tree usually do not change. In the present case study, the patient presents fever, productive cough, and tachypnea. A simple chest X-ray was performed because of the clinic, demonstrating right perihilar interstitial-alveolar opacity with right mediastinal deviation and asymmetry of pulmonary transparency. Due to the radiological finding, a computed tomography of the chest was requested, which showed the right lung of reduced volume. To provide a better understanding of the condition, the radiology team suggested computed angiotomography of the chest, which detected agenesis of the right pulmonary artery. The importance of the problem is to report a case of agenesis of the right pulmonary artery. (AU)

Aneurisma de Arteria Pulmonar como causa de muerte repentina: Reporte de un caso y revisión de literatura / Pulmonary Artery Aneurysm as a cause of sudden death: Case report and literature review

Resumen Objetivo: Correlacionar las generalidades de la etiología, patogenia, presentación clínica y métodos diagnósticos actuales disponibles para el aneurisma de arteria pulmonar con la muerte súbita o repentina de estos pacientes. Materiales y métodos: Se realizaron revisión del expediente clínico, análisis de la autopsia y revisión bibliográfica. Presentación de caso: Se presenta el caso de un masculino de 39 años con antecedente de hipertensión pulmonar que consultó por disnea súbita. Se abordó el caso como un tromboembolismo pulmonar. El paciente presentó una evolución clínica tórpida y falleció. La autopsia reveló un aneurisma de la arteria pulmonar. Conclusión: Los aneurismas de la arteria pulmonar son poco frecuentes. La presentación clínica es inespecífica. Los métodos diagnósticos más fiables son la sospecha clínica y los métodos de imagen, sin embargo siguen siendo motivo de muerte súbita y repentina; cuyo hallazgo es postmorten.

Abstract Objective: Correlate the generalities of etiology, pathogenesis, clinical presentation and current diagnostic methods available for pulmonary artery aneurysm with sudden death of these patients. Materials and methods: Review of medical record, autopsy analysis and scientific literature. Case presentation: A 39-year-old male with a history of pulmonary hypertension, who consulted for sudden dyspnea. The case was approached as a pulmonary thromboembolism. The patient presented bad clinical evolution and died. Autopsy revealed an aneurysm of the pulmonary artery. Conclusion: Aneurysms of the pulmonary artery are rare. The clinical presentation is nonspecific. The most reliable diagnostic methods are clinical suspicion and imaging methods, however they remain a cause of sudden death; whose finding is postmortem.

Left main coronary artery compression by the right pulmonary artery in a patient with congenital pulmonic stenosis / Compresión del tronco coronario izquierdo por la arteria pulmonar derecha en un paciente con estenosis pulmonar congénita

Abstract Congenital pulmonary stenosis (PS) can be associated with pulmonary artery (PA) dilatation. In some cases, this can cause compression of nearby structures including the left main coronary artery (LMCA). This compression causes angina and is considered an indication for surgical treatment. We present the case of a patient with PS and angina secondary to LMCA compression by the right PA and review the main indications and options for surgical treatment.

Resumen La estenosis pulmonar congénita se asocia a dilatación de la arteria pulmonar. En algunos casos esto puede causar compresión de las estructuras adyacentes incluyendo el tronco de la coronaria izquierda. Esta compresión causa angina y es considerada una indicación para tratamiento quirúrgico. Presentamos el caso de un paciente con estenosis pulmonar y angina secundaria a compresión del tronco de la coronaria izquierda por la arteria pulmonar derecha y revisamos las indicaciones y opciones de tratamiento quirúrgico.

Initial Experience in Chile with Stent Implantation in the Right Ventricle Outflow Tract in High-Risk Patients with Tetralogy of Fallot.

Tetralogy of Fallot (ToF) treatment is difficult in patients with surgical risk factors or unfavorable anatomy. Stent implantation in the right ventricular outflow tract (RVOT) is an option for these patients. We report our initial experience in Chile with RVOT stenting in patients with ToF. Retrospective and descriptive study conducted in three pediatric cardiovascular centers in Chile between 2012 and 2015, including all ToF patients with stent in the RVOT as first procedure. Clinical records, echocardiographic, interventional, and surgical reports were reviewed for demographics and information of RVOT and pulmonary arteries. 12 newborns with ToF were included (75% female). Median age was 20 days (1-70) and mean weight was 2178 g (1400-3414). Saturations increased after the procedure from 74.3% (55-88) to 88.5% (80-98%), (p < 0.01). No complications or mortality were related to interventions. Follow-up was 11 months (7-36). Median right and left pulmonary arteries Z-score increased from - 4.0 (- 5.2 to - 0.3) and - 1.5 (- 4.8 to - 0.26) to + 0.53 (0.0 to 2.2) and + 1.1 (0.5 to 2.9), (p < 0.05), respectively. Nakata index increased from 63 mm2/mm2 (35 to 143) to 162 mm2/mm2 (107 to 197), (p < 0.05). Surgical repair was performed at a median of 4 months (2-7). Transannular patch repair was necessary in all patients and there was no surgical mortality. RVOT stenting is a safe and useful option for patients with ToF and surgical risk factors or unfavorable anatomy. It increases the pulmonary blood flow, improving saturation and pulmonary artery growth as a bridge for surgical repair.

Left main coronary artery compression by the right pulmonary artery in a patient with congenital pulmonic stenosis.

Congenital pulmonary stenosis (PS) can be associated with pulmonary artery (PA) dilatation. In some cases, this can cause compression of nearby structures including the left main coronary artery (LMCA). This compression causes angina and is considered an indication for surgical treatment. We present the case of a patient with PS and angina secondary to LMCA compression by the right PA and review the main indications and options for surgical treatment.

La estenosis pulmonar congénita se asocia a dilatación de la arteria pulmonar. En algunos casos esto puede causar compresión de las estructuras adyacentes incluyendo el tronco de la coronaria izquierda. Esta compresión causa angina y es considerada una indicación para tratamiento quirúrgico. Presentamos el caso de un paciente con estenosis pulmonar y angina secundaria a compresión del tronco de la coronaria izquierda por la arteria pulmonar derecha y revisamos las indicaciones y opciones de tratamiento quirúrgico.

Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates.

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.

Bronchial-arterial-circulation-sparing Lung Preservation: A New Organ Protection Approach for Lung Transplantation.

BACKGROUND: Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function. METHODS: The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups. RESULTS: After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain. CONCLUSIONS: Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.

Voluntary running counteracts right ventricular adverse remodeling and myocyte contraction impairment in pulmonary arterial hypertension model.

AIM: Analyze the effects of voluntary running during the development of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) on the right ventricle (RV) structure, RV myocyte contractility and intracellular Ca2+ transient in rats with MCT-induced PAH. MAIN METHODS: Male Wistar rats were housed sedentary or with free access to a running wheel after MCT or saline injection for until HF or median end-point day of HF in sedentary animals (24 days). Echocardiographic examination and exercise tolerance test were carried out at specific time points of the experimental period. After euthanasia, the heart was dissected, weighed and processed for either histological or single myocyte contractility and intracellular Ca2+ transient analyzes. KEY FINDINGS: Voluntary running delayed the onset of HF (29 days) and the increase in pulmonary artery resistance, and improved exercise tolerance. In the median end-point day of HF, exercise retarded RV adverse remodeling (i.e. increase in extracellular matrix and collagen content). At this stage, exercise also delayed impairments in cell contractile function (i.e. amplitude and times to peak and to half relaxation) and intracellular calcium cycling (i.e. amplitude and times to peak and to half decay) in RV single myocytes. SIGNIFICANCE: Along with HF onset delay and physical effort tolerance enhancement, voluntary running during the development of PAH postpones pulmonary artery resistance increases, RV adverse remodeling and myocyte contractility and intracellular calcium cycling deterioration in rats. Therefore, self-paced intermittent exercise of high intensity may contribute positively to the health and survival of individuals with PAH.