Cellular Energy Production Different in PAH and CTEPH, Study Finds
Metabolic differences affecting energy production were observed in endothelial cells — the cells that line blood vessels — from patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
These distinctions could underlie differences in disease mechanisms and necessary treatment approaches, according to a recent study.
CTEPH and PAH are two rare, severe forms of pulmonary hypertension (PH). While the causes of each are different, both diseases involve restricted blood flow through the pulmonary arteries, which transport blood through the lungs.
There are two major metabolic pathways the body uses to produce energy. Oxidative phosphorylation occurs inside the mitochondria — the cell’s major energy production center — while glycolysis, a process of breaking down sugar to produce energy, happens outside the mitochondria. Under normal conditions, much of the body’s energy is produced in the mitochondria.
In PAH, endothelial cells (ECs) in the blood vessels undergo metabolic changes, resulting in a preference for glycolysis. These energy imbalances contribute to uncontrolled EC growth, or proliferation, resulting in blood vessel narrowing.
In contrast, less is known about EC metabolic changes in CTEPH.
To investigate metabolic differences between the two disorders, researchers in Spain now compared the metabolic characteristics of ECs collected from six PAH and 12 CTEPH patients.
As expected, PAH cells showed increased expression of genes responsible for making enzymes involved in glycolysis. Specifically, the expression of GLUT1, HK2, and LDHA was higher in PAH cells than in CTEPH or healthy cells.
PDHA1 is a protein that serves as a gatekeeper between glycolysis and mitochondrial energy pathways. When PDHA1 expression is reduced, glycolysis is promoted. Interestingly, higher levels of PDHA1 were observed in PAH compared with CTEPH or healthy cells, which suggests that mitochondrial forms of energy generation are also promoted in PAH.
This was supported by an observed increase in multiple oxidative phosphorylation complexes in PAH ECs, which are involved in mitochondrial energy production.
Expression of GLUD1, which is involved in glutamine metabolism — another form of energy production that occurs partially in the mitochondria — also was elevated in PAH cells.
Together, these data show that multiple metabolic pathways are different between PAH and CTEPH.
“A substantially different metabolic profile at the level of glycolysis, oxidative phosphorylation and glutamine metabolism is present in PAH-EC compared to CTEPH-EC,” the researchers wrote.
As noted, increased glycolysis can drive excessive cell proliferation — a major pathological feature of PAH.
Consistently, the researchers observed that more live PAH cells grew in cell culture than CTEPH or healthy cells. This effect was reversed when metabolism was blocked with inhibitors.
One of the inhibitors, called dichloroacetate (DCA), has previously shown beneficial effects in PAH patients. DCA results in PDHA1 activation, which enhances mitochondrial energy pathways and inhibits glycolysis.
Since CTEPH cells did not show the same metabolic changes, DCA may not be as beneficial for these patients.
“Based on the results of this study, showing [a difference in glycolysis] in CTEPH-EC compared to PAH-EC, blocking glycolysis may not be beneficial in CTEPH-EC and requires further investigation for the development of novel CTEPH treatments,” the researchers wrote.
Important to note is that PAH patients, on average, had more significant impairments in blood flow than CTEPH patients, which could indicate greater disease severity. This could contribute to the observed metabolic differences.
Nonetheless, the overall differences in metabolism between PAH and CTEPH suggest “differences in molecular mechanisms and regulatory pathways that could be important in disease pathology and in the development of curative treatments,” the researchers wrote.
Future work should verify the results in a larger number of patients, and seek to further understand the importance of the differences between PAH and CTEPH, the researchers noted.