A study recently published in Oxidative Medicine and Cellular Longevity exhibits differences in mitochondrial protein expression between lung cells from rats with pulmonary arterial hypertension (PAH) and those of healthy rats. This finding suggests a role of mitochondrial proteins in the pathogenesis of this disease and, therefore, possible use as biomarkers and new therapeutic targets.

This experimental research conducted by Wang and colleagues induced PAH in 6 rats via monocrotaline administration and compared them to a control group of 6 rats. Mitochondrial proteins were determined in both groups using a label-free quantification proteomic technique. The authors screened 123 coding genes that were downregulated in rats with PAH and 19 that were upregulated. This proportion shifted in the validation phase, with 6 upregulated mitochondrial genes (PSMD2, PSMC4, PSMC3, PSMC5, PSMD13, and PSMC2) and 3 downregulated genes (LIPE, CAT, and PRKCE) in the rats with PAH.

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Moreover, the authors hypothesized that microRNAs (miRNAs) may alter gene expression of the hub mitochondrial genes, with 32 miRNAs for the upregulated genes and 53 for the downregulated ones. An important realization was that 26 different miRNAs might regulate the CAT gene.

Finally, proteasome inhibitors such as bortezomib and carfilzomib were tested as potential PAH disease progression and reversion therapies. Although still limited, the drugs showed promising results by targeting the upregulated genes.

The roles of the mitochondria and mitochondrial protein structure have previously been established in multiple diseases, including degenerative and neoplastic processes, among others, but they had not been extensively studied in PAH. The interaction of hub mitochondrial genes with well-known actors in PAH could be determined.

The authors explained, “we found that the upregulated mitochondrial [differentially expressed proteins] were closely associated with ubiquitin-mediated proteolysis, [tumor necrosis factor] signaling pathway, [retinoic acid-inducible gene I]-like receptor signaling pathway, and [nuclear factor kappa B] signaling pathway.”

The study authors concluded, suggesting a novel therapeutic approach for PAH, that “clinical observational studies have found that the CAT gene is associated with pathophysiological processes in pulmonary vascular disease mediated by oxidative stress and is significantly downregulated in the development of emphysema, as well as in PAH and chronic thromboembolic pulmonary hypertension (CTEPH).“

“At the same time, high expression of CAT is an essential factor in the prognosis of patients with pulmonary hypertension,” they noted.

Reference

Wang J, Uddin MN, Li Q, et al. Identifying potential mitochondrial proteome signatures associated with the pathogenesis of pulmonary arterial hypertension in the rat model. Oxid Med Cell Longev. 2022;2022:8401924. doi:10.1155/2022/8401924