MTMR7 protein shows promise as PAH treatment in mice
Boosting protein's production reversed signs of disease in mouse model
Boosting the production of a protein called myotubularin-related protein 7 (MTMR7) reversed signs of pulmonary arterial hypertension (PAH) in a mouse model of the disease, a study shows.
MTMR7 suppresses the excess growth and migration of cells lining the arteries, which contribute to the narrowing of these blood vessels that drive high blood pressure in PAH.
“Our findings suggest that MTMR7 may be a novel potent target for the treatment of [PAH],” the researchers wrote. The study, “MTMR7 attenuates the proliferation and migration of pulmonary arterial smooth muscle cells in pulmonary hypertension by suppressing ERK/STAT3 signaling,” was published in Molecular and Cellular Biochemistry.
Pulmonary hypertension (PH) is a progressive disorder associated with high blood pressure in the pulmonary arteries, which carry blood from the heart through the lungs. The increased blood pressure in thes arteries means the right side of the heart must work harder to pump blood, which can eventually lead to heart failure. In PAH, a type of PH, high blood pressure is caused by the pulmonary arteries narrowing, which is mainly driven by the uncontrollable growth of cells — the pulmonary arterial smooth muscle cells (PASMCs) — that line them. While most standard PH treatments ease symptoms by relaxing and widening arteries to improve blood flow, they don’t address the abnormal growth of PASMCs.
“Identification of the underlying targets that can prevent the excessive [growth] and migration of PASMCs is urgently needed,” the researchers wrote.
MTMR7 is known to suppress the growth of cancer cells and some reports suggest the protein may be involved in stroke, suggesting a role in blood vessel-related diseases.
The benefits of boosting MTMR7 in PAH
Because the function of MTMR7 in PASMCs and PAH is unknown, researchers in China examined a mouse model of PAH induced via exposure to monocrotaline (MCT), a toxic chemical.
Initial experiments confirmed that MTMR7 was detected in the pulmonary arteries of healthy mice, its distribution suggesting it was localized in PASMCs. Mice with PAH-like disease had significantly lower MTMR7 levels than healthy mice.
Consistent with what’s observed in people with PAH, the mice had several signs associated with right heart strain, including a thicker muscle wall of the right ventricle (the heart’s lower chamber) and high blood pressure in the right ventricle during a heartbeat. When the mice were genetically engineered to overly produce MTMR7 within the pulmonary arteries, all these PAH signs were reversed.
A tissue examination agreed with these findings. Higher than normal MTMR7 levels suppressed MCT-induced enlargement of the right ventricle, along with muscle wall thickening and collagen deposition in pulmonary blood vessels. Collagen is typically elevated in scar tissue formed due to PAH.
When the researchers exposed lab-grown PASMCs to low oxygen — a known trigger of PAH — they observed a significant increase in cell growth and a significant reduction in MTMR7 levels. But inducing excessive MTMR7 production with a modified and harmless virus reversed this excess growth and migration of the PASMCs.
In experiments to understand the underlying mechanisms of MTMR7’s beneficial effects in PAH, the researchers found that the protein reduced the activity of the ERK1/2/STAT3 signaling pathway, which regulates cell growth, maturation, and survival.
“Our study highlights the [suppressive] role of MTMR7 in PH and in the [growth] and migration of PASMCs, and thus provides a novel potent therapeutic strategy for treating PH,” they wrote.
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