A new role for PPARγ in Pulmonary Arterial Hypertension (PAH)
By Megan Mayerle, PhD
March 25, 2019
Pulmonary arterial hypertension (PAH) is a form of pulmonary hypertension that results from the loss and narrowing of the lumen of small arteries of the lungs which causes an increase in blood pressure. Over time, this increased blood pressure can damage the heart. PAH generally affects young and otherwise healthy individuals and strikes women twice as often as men. Estimates indicate that there are between 10,000 and 20,000 PAH patients in the US.
While PAH is not yet understood at the molecular level, dysfunctional peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor that acts as a part of a transcription factor complex in vascular and other cell types, has been linked to many vascular diseases including PAH. Furthermore, in PAH, dysfunction of endothelial cells, the cells that line the interior of blood vessels, has been linked to the loss and narrowing of blood vessels, which leads to increased resistance to pulmonary blood flow and can culminate in heart failure and the need for a lung transplant.
In a study recently published in Cell Reports, lead author Dr. Caiyun Grace Li, corresponding author Dr. Marlene Rabinovitch, and colleagues reveal a new role for PPARγ, linking it to the cellular DNA damage response and to DNA repair.
Cellular proteins often function as part of protein-protein complexes. By placing a molecular "handle" on PPARγ, Dr. Li was able to isolate PPARγ from cells and determine what proteins it formed complexes with. She discovered that PPARγ formed a previously unknown complex with a group of cellular proteins that sense when DNA has been damaged, known as the MRN complex. She also identified an interaction with a protein called UBR5, an E3 ubiquitin ligase that helps regulate the abundance of many cellular proteins. These results were very intriguing, as a previous study had linked DNA damage to PAH pathogenesis, though the molecular mechanisms underlying this connection were unknown.
The authors knew that the MRN complex and UBR5 are both required for the activity of another protein called ATM, which is 'a first responder' to the DNA damage response. Li et al. used RNAi technology to experimentally decrease cellular levels of PPARγ, and chemical agents to damage DNA, and then monitored the behavior of the components of the DNA damage response. The researchers found that, in cells lacking PPARγ, the cellular abundance of, and thus function of, key proteins that respond to and repair DNA damage were altered. This result was novel as it showed that PPARγ exerts this function at the protein level, not at the transcriptional level, as it was previously thought to function, and suggested a new role for PPARγ in PAH pathogenesis.
Endothelial cells isolated from the lungs of PAH patients exhibit many pathological phenotypes including a loss of genome integrity, an increased propensity toward apoptosis, and a tendency to transform into other cell types. Unrepaired DNA damage could underlie many of these pathological changes. To test this, Li et al. looked for evidence of DNA damage in isolated endothelial cells from the lungs of PAH patients, and compared their findings to endothelial cells from control, non-diseased lungs. They found that the interactions between PPARγ and UBR5 were decreased, and many other cellular hallmarks of an impaired DNA damage response were present in the PAH cells. In other words, the cells were behaving as though they lacked normal PPARγ.
In addition to providing a clearer understanding of the role that PPARγ plays in PAH pathogenesis, these novel findings lay the groundwork for potential new PAH therapeutics and treatment strategies.