Pulmonary Hypertension Prevented, Treated by Macitentan in Systemic Sclerosis Mouse Model

A team of researchers from University College London and Actelion Pharmaceuticals showed that macitentan (Opsumit) can prevent pulmonary arterial hypertension (PAH) in a mouse model of systemic sclerosis (SSc) by preventing heart tissue remodeling and functional changes. The results were presented this week by E. Derrett-Smith at the 4th Systemic Sclerosis World Congress in Lisbon, Portugal.

The presentation was entitled “Macitentan responsiveness supports the validity of a murine model of pulmonary hypertension in scleroderma associated with altered TGFBETA/BMPRII signaling.”

The research team investigated a mutant mouse, called TβRIIδk-fib, that develops pulmonary hypertension (PH) after an injury to the endothelial cells lining the airway. Research had previously shown that the development of PH in these mice depends on an imbalance between the signaling molecules TGF-β and BMPRII.

Mice were divided into four groups. The first two groups received either macitentan treatment or a control injection daily, starting two days before the induction of PH. The last two groups also received macitentan or control injections daily, but the treatment did not start until eight days following the induction of endothelial injury.

Endothelial injury in both mutant and normal mice was induced using the compound SU5416. This led to increased cell division and expansion only in the mutant mice. After three weeks of treatment, the team assessed the development of PH by measuring cardiovascular function in live mice, and analyzing blood vessel architecture and the mass of the heart’s right ventricle. The gene expression in the right ventricle was also assessed.

All the mutant mice developed inflammation and a thickened smooth muscle layer around the blood vessels. In 21 percent of the arteries analyzed, researchers observed that the vessels were obstructed. In PH-affected mice, the right ventricle was found to weigh more than in normal mice; interestingly, however, PH mice treated with macitentan two days before the endothelial injury had normal right ventricle masses. Macitentan also lowered the right ventricle systolic pressure without changing the systemic arterial blood pressure. The largest effect was seen in mice where treatment started before the endothelial injury.

Macitentan-treated mice showed no signs of occlusion of their arteries. The team also reported an altered gene expression in the heart’s right ventricle, particularly in genes thought to be associated with heart tissue remodeling and heart failure.

The research team concluded that macitentan could prevent and treat tissue and heart function changes that typically accompany PH in this mouse model. Furthermore, researchers suggest that the model is a valid and valuable tool for studies on SSc-PAH treatment.