Metabolic theory of pulmonary arterial hypertension: connecting mitochondrial roles with disease control

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricular pressure overload and can lead to right-sided heart failure and death. A close link between PAH and cancer has been extensively suggested, with increasing evidence of a metabolic theory that underlies the pathogenesis of both diseases, mainly due to similarities in the processes responsible for triggering a hyperproliferative and apoptosis-resistant phenotype in both cardiopulmonary and malignant cells. Similar to cancer, abnormalities in mitochondrial biogenesis might lead to the following consequences: dysfunction of this organelle, which, in turn, causes the Warburg effect, a shift from mitochondrial respiration toward glycolysis, culminating in mitophagy in diseased pulmonary vessels and right ventricular cardiomyocytes. The role of these mitochondrial abnormalities offers new therapeutic avenues. Therefore, this study reviews the bases of mitochondrial derangements in PAH and explores the therapeutic implications of mitochondrial dysfunction and metabolic disturbances in cells from the pulmonary vasculature and right ventricular myocardium by addressing promising and challenging areas of investigation.La hipertensión arterial pulmonar (HAP) se caracteriza por una mayor resistencia vascular pulmonar, que provoca una sobrecarga de presión del ventrículo derecho (VD) y puede provocar insuficiencia cardíaca del lado derecho y la muerte. Se ha sugerido ampliamente un vínculo estrecho entre la HAP y el cáncer, con evidencia creciente de una teoría metabólica que subyace a la patogénesis de ambas enfermedades, principalmente debido a las similitudes en los procesos responsables de desencadenar un fenotipo hiperproliferativo y resistente a la apoptosis tanto en células cardiopulmonares como malignas. De manera similar al cáncer, las anomalías en la biogénesis mitocondrial pueden tener las siguientes consecuencias: Disfunción de este orgánulo, que a su vez provoca el efecto Warburg, un cambio de la respiración mitocondrial hacia la glucólisis, que culmina en una mitofagia en los vasos pulmonares enfermos y en los cardiomiocitos del ventrículo derecho. El papel de estas anomalías mitocondriales ofrece nuevas vías terapéuticas. Por lo tanto, este estudio revisa las bases de los trastornos mitocondriales en la HAP y explora las implicaciones terapéuticas de la disfunción mitocondrial y los trastornos metabólicos en las células de la vasculatura pulmonar y el miocardio del VD abordando áreas de investigación prometedoras y desafiantes.Sociedad Argentina de Fisiologí

Endocannabinoid System: Chemical Characteristics and Biological Activity

The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes. Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors. eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases. This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB

Role of Arbovirus Infection in Arthritogenic Pain Manifestation—A Systematic Review

The number of publications on the development of arthritic pain after CHIKV infection is increasing; however, there is still a gap in the pathophysiological mechanisms that explain these outcomes. In this review, we conducted a descriptive analysis of the findings of patients to understand their prognosis and to explore therapeutic options. Here, we searched the Cochrane, BVS, PubMed, and Scielo databases using the keywords “arthritis”, “pain”, “arbovirus”, “disease”, “arthritogenic”, and “arthralgia” during the 2000 to 2022 period. Descriptive analyses were conducted to understand the association between CHIKV infection and arthritogenic pain. The present study shows the persistence of acute phase signals for months, making the chronic phase still marked by the presence of arthralgia, often disabling under stimuli, such as temperature variation. CHIKV infection appears to be remarkably similar to rheumatoid arthritis, since both diseases share common symptoms. Once diagnosed, patients are mostly treated with analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease modifying anti-rheumatic drugs (DMARD). As there are no prophylactic measures or specific treatments for arboviruses, this study gathered information on the development and manifestations of arthritogenic pain

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment