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Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. 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 expression of the gene encoding the H2O2-producing enzyme Nox4, which is 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 in blood pressure seen 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. 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. Editor's summary: Obesity induces endothelial dysfunction that can lead to hypertension. Wolpe et al. 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 the expression of Nox4, 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 showed greater oxidative stress in the endothelium and developed hypertension. Moreover, Panx3 mRNA expression and Bcl6 protein abundance were decreased and Nox4 mRNA expression was increased in mice with diet-induced obesity, but not in mice with pharmacologically induced hypertension. Endothelial Panx3 and Bcl6 abundance were reduced in hypertensive, obese individuals, suggesting that reductions in endothelial Panx3 may drive obesity-associated hypertension. —Wei Wong [ABSTRACT FROM AUTHOR]

The article presents a study which showed that the up-regulation of kynurenine synthesis and its metabolism to kynurenine-carboxyketoalkene (Kyn-CKA) is an adaptive response that attenuates inflammation and protect tissues. Topics discussed include in vivo generation of Kyn-CKA, extraction of kynurenine and Kyn-CKA metabolites, and statistical analysis.