Porphyromonas gingivalis-Derived LPS Disrupts BH4–eNOS Signaling in Primary Human Umbilical Vein Endothelial Cells: Modulation by Sepiapterin and CDDO-Me
Year: 2026
Type: preprint
Abstract: Periodontitis is associated with vascular endothelial dysfunction and elevated cardiovascular risk, but the mechanisms by which Porphyromonas gingivalis-derived lipopolysaccharide (Pg. LPS) impair endothelial function remain poorly understood. We investigated whether Pg. LPS disrupts endothelial homeostasis through oxidative stress, tetrahydrobiopterin (BH4) metabolism, nitric oxide signaling, and glucose metabolism in primary human umbilical vein endothelial cells (HUVECs). In addition, we evaluated the protective effects of L-sepiapterin (a BH4 precursor) and the Nrf2 activator CDDO-Me. HUVECs were treated in vitro with Pg. LPS (10 μg/mL) for 12, 24, or 48 h, with or without L-sepiapterin (100 μM) or CDDO-Me (100 nM), and outcomes were assessed by qRT-PCR, Western blot, ELISA, and biochemical assays. Pg. LPS activated TLR4/NF-κB signaling, increased ROS and ICAM-1, suppressed Nrf2. It produced a biphasic disruption of GCH1/DHFR expression; reduced extracellular BH4, eNOS expression, and eNOS dimerization; increased iNOS expression; altered nitrite output; and increased PEA-15 and GLUT1 expression and glucose uptake. L-Sepiapterin more consistently restored BH4 and eNOS coupling, whereas CDDO-Me more effectively suppressed iNOS and oxidative/inflammatory markers. These findings identify disruption of the GCH1/DHFR–BH4–eNOS axis as a key mechanism of Pg. LPS-induced endothelial dysfunction and suggest that targeting BH4 metabolism and Nrf2 signaling may be complementary therapeutic strategies for periodontitis-associated vascular disease.
Source: Preprints.org
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225808400
Cites:
Cited by:
Related to: