I don’t normally write about pre-clinical research but my friend and CardioExchange colleague John Ryan has been on a tear lately (he even won a Young Investigator award from the AHA last year) with some fascinating and potentially important research. Briefly, and, I hope, not too simply, Ryan’s research may have uncovered a key mechanism underlying the pathogenesis of pulmonary arterial hypertension. And, if the research holds up, it may offer a new therapeutic target for this rare but deadly disease, for which there are no good therapies available.
Ryan’s research was performed in Stephen Archer’s lab while he was a cardiology fellow at the University of Chicago. (Ryan is now on the faculty at the University of Utah and Archer has moved to Queen’s University in Ontario.) The research has focused on the previously unappreciated role of mitochondria in pulmonary artery smooth muscle cells (PASMCs). Ryan and colleagues found that proliferation of PASMCs– a key contributor to the pulmonary vascular obstruction that is the hallmark of PAH– requires mitochondrial division in order to occur, since the daughter cells will each require mitochondria. They identified a protein, called DRP1, that leads to mitochondrial division (fission). They then tested a DRP1 inhibitor, called Mdlv-1, that prevented PASMC proliferation in rodent models and in cultured human cells.
“Pathological rates of mitochondrial fission in PAH may present an ‘Achilles heel’ for these fast-growing cells,” the investigators wrote last year. “Inhibiting mitochondrial fission constitutes a novel therapeutic strategy in PAH.”
In a recent paper, Ryan and colleagues looked at the effects of another protein, MFN2, and its impact on mitochondria in female rats with PAH and in female patients with PAH. They found that MFN2, which promotes mitochondrial fusion (the opposite of division), had antiproliferative effects on PASMCs in rodents and in humans and caused regression of PAH in rodent models of the disease.
It should be emphasized that there is a long way to go before we know if this early work fulfills its promise. It’s also possible that this research may have implications beyond PAH, since this pathway seems to have a general antiproliferative effect in vascular beds, according to Archer. But whatever the ultimate outcome of this research, I feel confident that we are looking at the early stage of a promising career.