Enzyme in Lung Arterial Muscle Cells May Be Therapeutic Target

Rac1, an enzyme involved in blood pressure regulation, is overly active in pulmonary artery smooth muscle cells (PASMCs) — the cells that line the walls of pulmonary arteries — of people with pulmonary arterial hypertension (PAH) and a mouse model of pulmonary hypertension (PH), a study shows.

Notably, suppressing Rac1 specifically in smooth muscle cells was found to lessen key features of hypoxia-induced PH in mice, suggesting that this enzyme actively contributes to the development of this disease. Hypoxia refers to low oxygen conditions and chronic hypoxia is a common cause of PH.

These findings, along with previous data suggesting that Rac1 contributes to PH, point to this enzyme as a new potential therapeutic target of PH, the researchers noted.

Further research is needed to confirm Rac1’s therapeutic relevance.

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The study, “Smooth muscle Rac1 contributes to pulmonary hypertension,” was published in the British Journal of Pharmacology.

PAH, a type of PH, is characterized by dysfunction of endothelial cells — the cells that line blood vessels — and the narrowing of pulmonary arteries, restricting blood and oxygen flow and raising blood pressure (hypertension).

This arterial narrowing is the result of excessive blood vessel contraction and remodeling, a process that involves the uncontrolled growth of PASMCs, progressively thickening the arterial walls.

In a previous study, a team of researchers in France showed that an enzyme called Rac1 regulates arterial blood pressure outside the lungs by modulating nitric oxide-mediated relaxation of arterial smooth muscle cells.

Nitric oxide (NO) is a gas naturally found in the body that works as a vasodilator: it relaxes and widens blood vessels, so that blood flows more easily through them with less pressure.

Since NO abnormalities are known to contribute to PH, the same team now evaluated the role of Rac1 in PASMCs and its involvement in PAH.

They first found that Rac1 was overactivated in PASMCs of both mice with hypoxia-induced PH and people with PAH of unknown cause, compared with their unaffected counterparts.

To better understand the enzyme’s role, the team then analyzed the effects of genetically modifying mice to lack Rac1 specifically in smooth muscle cells.

Results showed that this Rac1 deficiency significantly reduced key features of PH and limited pulmonary arterial remodeling, namely PASMCs growth, and the production of reactive oxygen species, or ROS, in mice exposed to chronic hypoxia.

ROS are potentially harmful molecules that stimulate muscle growth and that when overly produced may lead to oxidative stress, a type of cellular damage that is a known contributor to PAH.

Notably, pulmonary arteries of mice lacking Rac1 specifically in smooth muscle cells showed similar contractile responses to those of normal mice. However, Rac1 deficiency prevented hypoxia-induced defects in endothelial/NO-dependent arterial relaxation, “suggesting a role of PASMC Rac1 upstream to the effect of NO on PASMC,” the researchers wrote.

These findings suggest that Rac1’s excessive activation in PASMCs “plays a causal role in PH by favoring ROS-dependent [pulmonary artery] remodeling and endothelial dysfunction induced by chronic hypoxia,” they added.

In addition, previous studies have suggested that Rac1 in endothelial cells or in other pulmonary artery cells contributes to PH development, “supporting the idea that pharmacological [suppression] of Rac1 may restrict disease progression and improve clinical outcomes of PH patients,” the team wrote.

More studies are needed to confirm the therapeutic potential of blocking Rac1 in PH, but first, “specific and potent Rac1 inhibitors” suitable for animal studies need to be developed, the researchers concluded.