In a study entitled “Sirtuin 3 Deficiency Is Associated with Inhibited Mitochondrial Function and Pulmonary Arterial Hypertension in Rodents and Humans” published in Cell Metabolism, researchers report a mitochondrial protein, Sirtuin 3, as the underlying link between inhibited mitochondrial function and pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is characterized by increased blood pressure in the lungs’ vasculature. This is caused by uncontrolled proliferation of cells within the walls of lung arteries leading to obstruction of the vessels. To allow blood flow, the heart has to make an additional effort to pump blood to the lungs. As a consequence, the extra workload performed by the heart induces hypertrophy in the heart’s right ventricle, causing right heart failure.
The uncontrolled proliferation of cells within the pulmonary vasculature is similar to proliferation observed in cancer cells. Accordingly, suppression of mitochondria metabolic functions was previously observed in both animal models of PAH and cancer models, with reactivation of mitochondria function an efficient therapeutic strategy. However, what causes this metabolic remodeling in PAH patients’ pulmonary arteries and extra pulmonary tissues remained unknown prior to this new research.
In this study, the team of researchers at the Department of Medicine at the University of Alberta in Edmonton, Canada found that a mitochondria deacetylase, sirtuin 3 (SIRT3), is the missing link. Specifically, mice lacking SIRT3 exhibit higher levels of acetylation, leading to suppression of key mitochondria functions, including inhibition of mitochondria-dependent apoptosis and activation of mitochondria-proliferative pathways, thus contributing to enhanced vascular remodeling and PAH development. The team analyzed human PAH pulmonary artery smooth muscle cells (PASMC) and rats with PAH and observed decreased expression of SIRT3. As a result, reestablishing SIRT3 levels via adenovirus gene therapy reversed disease phenotype.
E.D. Michelakis, the study’s lead author, commented, “Our previous work had suggested that mitochondria, the organelles in the cell that regulate metabolism, are involved in the development of pulmonary hypertension, but we did not know exactly how. We also knew that mitochondria are involved in the development of both cancer and diabetes.”
“So we looked at a key regulator of mitochondrial function, a protein called Sirtuin3. We found that in lab models of pulmonary hypertension and, more importantly, in tissues from 160 patients, Sirtuin3 was present in lower amounts and was less active in lab models and patients with pulmonary hypertension than in those without the disease. We were intrigued to find that lab models that just lacked Sirtuin 3, developed pulmonary hypertension. The same models have been shown by other researchers to develop diabetes and cancer,” added Roxane Paulin, a postdoctoral fellow in Michelakis’ laboratory and study first author study.
“When we used gene therapy to deliver the missing Sirtuin 3 to the lungs of lab models of pulmonary hypertension with an inhaled virus, we found that the disease improved significantly two weeks later, opening the possibility for similar gene therapy approaches to patients,” said Paulin.
Finally, the authors analyzed a cohort of 162 patients with PAH and found PAH was associated with a loss-of-function SIRT3 polymorphism, linked to metabolic syndrome.
Michelakis added, “This work offers strong support to the theory that pulmonary hypertension has a metabolic basis and may facilitate our efforts to diagnose and treat the disease. The fact that we found a variant Sirtuin 3 gene that produces a defective Sirtuin 3 protein, (which has also been found in patients with metabolic syndrome, a form of diabetes) in the blood cells of many patients with pulmonary hypertension, suggests that it may be easy to identify the precise patients that may benefit from gene therapy the future.”