Small protein may offer way of preserving heart function in PH

MCJ levels seen to rise in low oxygen, mice lacking protein are protected

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A scientist works with petri dishes in a lab along side a rack of vials filled with blood.

A protein known as MCJ might be a target of treatments needed to preserve heart function in people with pulmonary hypertension (PH), a study reports.

Elevated levels of MCJ were found in the lung tissue of individuals affected by the low oxygen conditions of chronic obstructive pulmonary disease (COPD), mice exposed to low oxygen, and in the heart of a pig model of PH. Moreover, heart function was preserved in mice lacking MCJ, and the animals were protected from heart and lung changes induced by low oxygen.

“These results therefore suggested that the MCJ protein might be involved in pulmonary hypertension,” Ayelén M. Santamans, PhD, the study’s first author at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III in Madrid, said in a press release. “The lack of cardio-specific treatments for this disease spurred us to pursue this line of research.”

The study, “MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension,” was published in the journal Science Advances.

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PH is marked by elevated blood pressure in the arteries that carry deoxygenated blood through the lungs. As a result, the heart’s right ventricle is under continuous strain as it works harder to pump blood.

Low levels of oxygen, a condition known as hypoxia, can trigger PH, which is a concern for people living at high altitudes as well as those with certain lung conditions, including idiopathic pulmonary fibrosis (scarring) and COPD.

Most approved PH treatments work to relax and widen arteries to improve blood flow and lower blood pressure, but they only mitigate some disease symptoms. A risk of heart failure remains considerable.

“Consequently, it is essential to gain a deeper understanding of the cardiac molecular mechanisms involved in PH,” the team wrote.

MCJ, or methylation-controlled J, is a small protein found in the inner membrane of mitochondria, the structures within cells that produce energy. Studies suggest MCJ regulates mitochondrial metabolism and acts like a brake under difficult metabolic conditions that affect mitochondrial function.

Still, its role in modulating mitochondrial responses to low oxygen levels, a challenge for mitochondria within heart muscle cells, remains unexplored.

Initial experiments found that elevated MCJ expression (production) correlated with the likelihood of more severe acute COPD exacerbations, a sudden worsening of lung symptoms. High MCJ levels also related to a low diffusing capacity of the lung for carbon monoxide, an indicator of impaired transfer of gas from the air into the bloodstream.

In a PH pig model, in which the pulmonary artery was restricted by banding, MCJ expression rose in muscles of the heart’s right ventricle (RV). Elevated MCJ levels also were noted in the heart and lungs of mice exposed to chronic hypoxia.

Heart muscles protected in mice lacking MCJ after hypoxia exposure

Next, healthy mice exposed to chronic hypoxia showed a thickening of the right ventricle muscle (hypertrophy) and reduced function. In contrast, mice lacking MCJ living under the same conditions showed no signs of hypertrophy, and their right ventricle function was preserved.

Only healthy mice, and not those without MCJ, eventually developed PH after chronic hypoxia. Consistently, chronic hypoxia caused changes to the structures of tiny blood vessels within the lungs and triggered an influx of immune cells. Such structural changes were absent in mice lacking MCJ, and they had less inflammation.

In a more severe PH mouse model, which combined hypoxia with the chemical Sugen 5416, mice lacking MCJ showed preserved right ventricle function despite established hypertrophy. This provided “further support for MCJ modulation as a promising therapeutic avenue,” the scientists wrote.

Blocking MCJ production, specifically in heart muscle cells of mice, effectively counteracted hypoxia-induced right ventricle hypertrophy and dysfunction, despite elevated pulmonary blood pressure. Re-introducing the protein to MCJ-negative mice led to impaired heart function without changes in blood vessel structure.

“Our results identify a cardiac-specific role of MCJ and emphasize that manipulating cardiac MCJ expression could offer a relevant approach to rescue RV systolic dysfunction,” the team noted.

Further experiments showed that the MCJ deficiency increased the levels of reactive oxygen species, the highly reactive chemicals formed during metabolism. This, in turn, triggered the activation of the mTOR pathway, increasing levels of the HIF-1-alpha protein, a crucial mediator of heart protection in response to oxygen levels.

“These findings offer valuable insights into potential therapeutic strategies for addressing cardiovascular complications associated with chronic hypoxia,” the scientists wrote.

A Conversation With Rare Disease Advocates