MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

Estudio del gen BMPR2 en pacientes con hipertensión arterial pulmonar / Study of the BMPR2 gene in patients with pulmonary arterial hypertension

IntroducciónLas mutaciones del gen que codifica el receptor 2 de las proteínas morfogénicas del hueso (BMPR2) contribuyen a la patogénesis de la hipertensión arterial pulmonar en sus formas familiar (HAPF) e idiopática.MétodoCon el objetivo de profundizar en el conocimiento de dichos factores genéticos en nuestro medio, se estudió el gen BMPR2 en 17 pacientes con hipertensión arterial pulmonar, 8 con HAPF y 9 con hipertensión arterial idiopática esporádica. Adicionalmente, se analizó si la presencia de mutaciones del gen BMPR2 se asociaba a cambios en la capacidad de difusión del CO a fin de evaluar el interés de esta medición en el diagnóstico preclínico.ResultadosSe detectaron las mutaciones R491Q y R211X en 2 pacientes con HAPF (prevalencia 25%), y la mutación R332X en un caso de hipertensión arterial idiopática (prevalencia 11%). El estudio familiar del paciente con la mutación R491Q demostró la presencia de la misma en 14 de los 28 sujetos estudiados, de los cuales 5 presentaban la enfermedad (penetrancia 36%). En dicha familia se observó un descenso de la relación en la capacidad de difusión del CO/volumen alveolar en los familiares asintomáticos que expresaban la mutación, comparado con los que no la expresaban (88±5% y 104±9% del valor de referencia, respectivamente; p<0,01).ConclusiónConcluimos que la frecuencia de mutaciones del gen BMPR2 en los pacientes con HAPF estudiados es inferior a la descrita previamente. El descenso del volumen alveolar observado en portadores de la mutación asintomáticos sugiere cierto grado de alteración vascular pulmonar, por lo que su medición podría ser útil en el estudio familiar de la HAPF(AU)

IntroductionMutations of the gene that code bone morphogenic protein type 2 receptor (BMPR2) are involved in the pathogenesis of pulmonary arterial hypertension (PAH), both in its familial (FPAH) and its idiopathic (IPAH) forms.MethodWith the aim of increasing the knowledge of these genetic factors in our area, the BMPR2 gene was studied in 17 patients with PAH, 8 with FPAH and 9 with sporadic IPAH. Additionally, a study was made to see whether the presence of BMPR2 mutations was associated with changes in the CO diffusing CO (DLCO) with the aim of evaluating the interest in this measurement in the pre-clinical diagnosis.ResultsR491Q y R211X mutations were detected in 2 patients with FPAH (prevalence, 25%), and the R332X mutation in one case of IPAH (prevalence, 11%). The familial study of the patient with the R491Q mutation, 14 of the 28 subjects studied had the mutation, and 4 had the diseases (penetration, 36%). A decrease in the DLCO/alveolar volume (KCO) ratio was observed in asymptomatic family members who expressed the mutation, compared to those who did not express it (88±5% and 104±9% of the reference value, respectively; P<0.01).ConclusionWe conclude that the frequency of mutations in the BMPR2 gene in the patients studied with FPAH is lower than was previously described. The decrease in the KCO observed in asymptomatic carriers of the mutation suggests a certain level of pulmonary vascular changes, therefore its measurement could be useful in the familial study of FPAH(AU)