A new study published in September’s issue of the American Journal of Respiratory and Critical Care Medicine, entitled, “The Sphingosine Kinase 1 / Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension” reports the discovery of two novel therapeutic targets to treat pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a result of elevated blood pressure in the arteries that supply the lungs, causing their walls to thicken. In cases where pressure levels are too high, ultimately the heart can’t keep up and less blood is carried through the pulmonary arteries leading to oxygen deficits and symptoms of dizziness and shorts of breath. A fatal outcome culminates with heart failure in these patients.
High blood pressure in the lungs is caused by a narrowing of the pulmonary blood vessels. Underlying this phenotype is the abnormal proliferation of involuntary non-striated muscle cells within the pulmonary artery walls. Arterial smooth muscle cells trigger vasodilation and vasoconstriction when responding to carbon dioxide or oxygen, respectively.
A team of scientists from UIC College of Medicine, investigated the molecular mechanisms responsible for the abnormal proliferation of smooth muscle cells in the pulmonary artery.
The enzyme sphingosine kinase 1 (SpkK1) synthesizes Sphingosine-1-phosphate (S1P), an important lipid mediator that promotes cell proliferation, migration and angiogenesis in cancer. Thus, the authors hypothesized “The characteristic proliferation of cells that line the blood vessels in pulmonary hypertension is similar to the abnormal growth and reproduction of cells that form cancerous tumors. We wanted to see if sphingosine kinase 1 and S1P were involved in the development of pulmonary arterial hypertension,” noted Jiwang Chen, first author and research assistant professor of critical care medicine, sleep and allergy in the UIC College of Medicine.
Chen and colleagues found in lung tissue of PAH patients a significant increase in the expression of both the enzyme and S1P. This increase was also observed in mouse and rat models of PAH.
The relevance of these findings was further confirmed by in vivo studies, using drugs that suppress S1P receptors in smooth muscle cells, and with “knock-out” mice that lack the gene for the enzyme, SpkK1: in low-oxygen conditions (to induce PAH disease) both experimental approaches prevented mice from developing PAH.
“Our results yield two new potential targets for the development of drugs to treat or prevent the progression of pulmonary arterial hypertension,” Chen said. “By blocking the binding site for S1P or suppressing the production of S1P, like we did in our experimental rodent model, we can reduce the proliferation of pulmonary artery smooth muscle cells, which is a major contributor to pulmonary hypertension.”