Page 23 - The Hormel Institute 2024 Annual Report

Pulmonary hypertension is a progressive pul- monary vascular disease with no cure that leads to death if left untreated. The disease
has a very poor prognosis with a median survival of only 2.8 years and a 34% 5-year survival rate.
Pulmonary hypertension is characterized by ele- vated pulmonary arterial pressure in pulmonary arteries (vessels in the lungs), which eventually results in right heart failure. Pulmonary vascular remodeling is one of the main causes of in- creased pulmonary arterial pressure. The current treatment options include lung transplantation and targeting the side effects of vasoconstriction by producing pulmonary vasodilation rather than focusing on pulmonary vascular remodeling.
Despite the recognition that pulmonary vascular remodeling is an essential feature of pulmo- nary hypertension that directly contributes to unacceptably high mortality, the mechanistic basis for severe pulmonary vascular remodeling is poorly understood. These findings mandate a thorough interrogation of this key feature of pul- monary hypertension pathobiology and highlight the need to develop novel remodeling-targeted therapeutically effective strategies for patients with pulmonary hypertension.
We aim to find novel therapeutic targets that can be developed into new effective treatment strategies to decrease pulmonary vascular remodeling in patients with pulmonary hypertension and cure the disease.
Pulmonary vascular remodeling results from
the imbalanced proliferation/death ratio in cells inside the pulmonary artery. There are three types of cells inside the pulmonary artery: endothelial cells (the first layer to blood flow), smooth muscle cells, (the second layer to blood flow)
and fibroblasts (the third layer to blood flow). Endothelial cells are the first to sense changes
in the blood flow during the initiation of the disease. They change their behavior, morphol- ogy, and properties by undergoing a transition from slowly growing, normal endothelial cells,
to highly proliferative, abnormal cells. Increased cell proliferation and decreased cell death lead
to the narrowing and eventual obstruction of small pulmonary arteries, which directly increase pulmonary arterial pressure.
Calcium is a major stimulus for cellular prolif- eration and phenotypic transition in most cells, including lung endothelial cells. In our study, we discovered that removal of extracellular calcium prevents cells from undergoing the transition. Moreover, we identified specific calcium chan- nels (store-operated calcium channels) that are responsible for calcium influx into the cell and promotion of cell transition from normal state
to abnormal condition. These calcium channels consist of different combinations of components named STIM and Orai. By blocking the STIM or Orai genes, we demonstrated that cell transition was abolished. Our findings are similar to cancer studies where STIM and Orai are involved in transition of normal cells to cancer cells. The manuscript summarizing the results from this study is under submission to a scientific journal.
| 23