A Novel Role for the Small Molecule Cinnamaldehyde in Protecting Against P. gingivalis–Induced Endothelial Dysfunction in Mice: Involvement of PPARγ/Akt/eNOS and Nrf2/ARE Signaling

Background: Cardiovascular disease (CVD) remains the leading global cause of mortality, with endothelial dysfunction as an early driver of pathology. Periodontal disease (PD) and its pathogen Porphyromonas gingivalis (Pg) are increasingly associated with metabolic disturbances and vascular injury, yet the combined impact of microbial and dietary stressors has not been mechanistically defined. Methods: In this 24-week study, mice were subjected to chronic Pg infection with or without a high-fat diet (HFD). Metabolic profiling, cytokine analyses, molecular signaling assessments, and ex vivo vascular reactivity studies were performed to evaluate systemic and vascular outcomes. Results: Pg infection induced metabolic alterations and vascular inflammation, while HFD alone caused obesity, insulin resistance, dyslipidemia, and impaired endothelial relaxation. Combined Pg infection and HFD produced the most severe phenotype, with synergistically elevated cytokines, heightened TLR4/NF-κB activation, marked suppression of PPARγ and Nrf2 signaling, reduced eNOS expression, and diminished nitric oxide bioavailability. Cinnamaldehyde (CNM) supplementation improved metabolic indices, reduced inflammatory cytokines, restored PPARγ and Nrf2 activation, enhanced Akt-mediated eNOS phosphorylation, and normalized endothelial-dependent vasorelaxation. Conclusions: Pg infection and HFD act as synergistic metabolic and vascular stressors that accelerate endothelial dysfunction through coordinated disruption of PPARγ/Akt/eNOS and Nrf2 pathways, while CNM provides substantial protective effects.