The team of Dr. Guadalupe Sabio, from the CNIC, in collaboration with Dr. Eduardo Oliver, a researcher at the Margarita Salas Center for Biological Research (CSIC), has discovered a possible therapeutic target against pulmonary hypertension. The work, published in the journal Science Advances, identifies the first target capable of saving cardiac function in this disease, which represents hope in the fight against this rare but lethal pathology for which there is currently no treatment.
Pulmonary hypertension is characterized by high pressure in the arteries leading to the lungs, causing the heart to be continually overworked. It affects between 15 and 50 people per million inhabitants, with an estimated prevalence in Spain of 1.6 cases and an incidence (new cases diagnosed per year) of 0.3 per 100,000 inhabitants.
Despite being a rare disease, sufferers often face symptoms that significantly affect their quality of life: shortness of breath, dizziness, and fainting, and a transplant may even be necessary to prevent the patient's death.
Several risk factors may contribute to its development, such as smoking, being overweight, the existence of previous diseases such as COPD, genetic predisposition, or being exposed to low oxygen levels in high altitude areas.
So far, existing therapies target the lung, aiming to lower blood pressure. However, these strategies do not seem to improve cardiac function, making heart failure the main cause of death in these patients. "On most occasions, patients with pulmonary hypertension are diagnosed too late when the heart is already starting to become dysfunctional and existing therapies are less effective. This is why it is vitally important to find new targets to address the cardiac dysfunction that occurs in advanced stages of the disease," says Oliver, head of the Experimental Pharmacology and New Targets in Cardiopulmonary Disorders group at the CIB Margarita Salas and collaborator in this study.
Following this premise and studying samples from patients with pulmonary hypertension secondary to COPD, this group of researchers led by Dr. Guadalupe Sabio of the CNIC discovered that the mitochondrial protein levels called MCJ were elevated. The same occurred in mice exposed to low oxygen levels and in pigs with associated cardiac damage, so, says Ayelen Santamans, first author of the study, "these results suggest that the MCJ protein could be involved in pulmonary hypertension. The lack of cardio-specific therapies motivated us to move forward in that direction."
Once the involvement of MCJ was confirmed, "modulating the expression of this mitochondrial protein was a possible therapeutic strategy worth testing in our animal models of pulmonary hypertension," says Oliver. The work demonstrates that modulating the levels of the mitochondrial MCJ protein in the heart can preserve cardiac function despite lung damage. Such protection is caused by activating a signaling pathway essential for adaptation to low oxygen levels, which prepares the heart to function properly in the face of oxygen deprivation.
These findings could open new doors for possible therapeutic interventions against pulmonary hypertension as they offer the first target capable of saving cardiac function in this lethal disease.
This study was funded by the Spanish Ministry of Science and Innovation (RED2022-134397-T, MINECO-PID2019-104399RB-I00, PGC2018-097019-B-I00, RYC202020-028884-I), the IMPACT-2021 project (PMP21/00057), the Fundación Jesús Serra, EFSD/Lilly European Diabetes Research Programme, the Fundación BBVA, the Comunidad de Madrid and the AECC.
Reference: A mitochondrial target for cardiac intervention in pulmonary hypertension. Ayelén M. Santamans, Beatriz Cicuéndez, Alfonso Mora, Sanela Rajlic, María Crespo, Paula Vo, Madison Jerome, Álvaro Macías, Juan Antonio López, Magdalena Leiva, Susana F. Rocha, Marta León, Elena Rodríguez, Luis Leiva, Aránzazu Pintor Chocano, María Villalba-Orero, Inés García Lunar, Ana García-Álvarez, Pablo Hernansanz-Agustín, José Antonio Enriquez, Víctor I. Peinado, Joan Albert Barberá, Borja Ibañez, Jesús Vázquez, Jessica B. Spinelli, Andreas Daiber, Eduardo Oliver, Guadalupe Sabio (2024) Science Advances.