Pannexin channel protein may protect against obesity-related hypertension, researchers suggest

Endothelial pannexin 3 (Panx3) and Bcl6 abundance were reduced in hypertensive, obese individuals, indicating that reductions in endothelial Panx3 may drive obesity-associated hypertension.

"Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity," Abigail G. Wolpe, University of Virginia School of Medicine, Charlottesville, VA, USA, and colleagues wrote.

Obesity induces endothelial dysfunction that can result in hypertension. Dr. Wolpe and the team uncovered a role for Panx3 as a scaffolding protein that limits oxidative stress in the endothelium and hypertension.

Panx3 bound to and stabilized the transcriptional repressor Bcl6, which suppressed Nox4 expression, the gene encoding a hydrogen peroxide–producing enzyme. Mice lacking Panx3 in endothelial cells or treated with a peptide that disrupted the Panx3-Bcl6 interaction demonstrated greater oxidative stress in the endothelium and developed hypertension. Furthermore, there was a decrease in Panx3 mRNA expression and Bcl6 protein abundance, and Nox4 mRNA expression was increased in mice with diet-induced obesity, but not in mice with pharmacologically induced hypertension.

In the study, the researchers report that the abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized Panx3 and that Bcl6 transcriptional activity protects against vascular oxidative stress.

Key observations were as follows:

• Consistent with data from obese, hypertensive humans, mice with an endothelial cell–specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH.
• Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation.
• Panx3 deficiency was associated with increased gene expression encoding the H2O2-producing enzyme Nox4, normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature.
• Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and blood pressure in mice with endothelial Panx3 deficiency.
• Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity.

Using pharmacological and genetic approaches, the researchers demonstrated the Panx3-Bcl6 interaction as a regulator of vascular oxidative stress and systemic blood pressure. The study findings illuminate the dysregulation of Panx3/Bcl6/Nox4 as a pathway by which obesity can drive endothelial dysfunction and hypertension.

"Together, these data suggest that Panx3 oligomers exhibit diverse stoichiometric," the research group concluded. "In the endothelium, there is no direct evidence for channel functionality, and we instead posit that Golgi-localized Panx3 protects against oxidative stress in the cardiovascular system through protein-protein interactions with Bcl6."

Reference:

Wolpe, A. G., Luse, M. A., Baryiames, C., Schug, W. J., Wolpe, J. B., Johnstone, S. R., Dunaway, L. S., Juśkiewicz, Z. J., Loeb, S. A., Askew Page, H. R., Chen, L., Sabapathy, V., Pavelec, C. M., Wakefield, B., Cifuentes-Pagano, E., Artamonov, M. V., Somlyo, A. V., Straub, A. C., Sharma, R., . . . Isakson, B. E. (2024). Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress. Science Signaling. https://doi.org/adg2622