The gastrin-releasing peptide receptor antagonist RC-3095 reduced atherosclerotic lesions in mice by suppressing inflammatory responses in blood vessel and immune cells triggered by periodontal bacteria.
Reduced atherosclerotic lesion areaRC-3095 decreased plaque buildup in mice with bacteria-accelerated atherosclerosis while suppressing two key inflammatory pathways (NF-κB and MAPK) in both endothelial cells and macrophages.
What the researchers found
RC-3095 significantly reduced P. gingivalis LPS-induced leukocyte adhesion to endothelial cells by suppressing NF-κB-dependent expression of adhesion molecules ICAM-1 and VCAM-1. It also blocked M1 macrophage polarization by inhibiting both MAPK and NF-κB signaling pathways.
In ApoE-knockout mice on a high-fat diet, RC-3095 decreased the area of atherosclerotic lesions that were accelerated by P. gingivalis LPS injections, and lowered ICAM-1 and VCAM-1 expression in aortic tissue. These results demonstrate that blocking the gastrin-releasing peptide receptor interrupts multiple inflammatory steps in bacteria-driven atherosclerosis.
Why it matters
The link between periodontal disease and cardiovascular disease is well established but poorly treated. Current approaches address either the gum infection or the heart disease separately. RC-3095 targets the inflammatory connection between the two, potentially offering a novel therapeutic strategy that addresses the root cause of bacteria-driven cardiovascular damage through peptide receptor modulation.
How the study worked
Researchers tested RC-3095 in three systems: (1) human umbilical vein endothelial cells (HUVECs) and rat aortic endothelium to assess leukocyte adhesion; (2) THP-1 cells polarized into M1 macrophages by bacterial LPS exposure; and (3) ApoE-knockout mice on a high-fat diet receiving P. gingivalis LPS injections with or without RC-3095. Atherosclerotic lesion area, adhesion molecule expression, and inflammatory signaling pathways were assessed.
What this study cannot tell us
This is a preclinical study using cell cultures and a mouse atherosclerosis model. ApoE-knockout mice develop artificially accelerated atherosclerosis that differs from human disease progression. The P. gingivalis LPS injection model doesn't fully replicate chronic human periodontal disease. Dosing, pharmacokinetics, and potential off-target effects of RC-3095 in humans were not assessed.
How to read the evidence
This is a preclinical study combining in vitro cell experiments with an in vivo mouse model. While the multi-system approach provides strong mechanistic evidence, the results have not been validated in humans or clinical settings.
When this study was published
Published in 2024, this is recent work that connects the growing fields of oral-systemic disease and peptide receptor pharmacology, with potential implications for the large population of patients with both periodontal and cardiovascular disease.
The bigger picture
Gastrin-releasing peptide (GRP) and its receptor bombesin receptor subtype 2 have been studied primarily in cancer, but their role in inflammation is gaining recognition. This study extends the therapeutic potential of GRP receptor antagonists to cardiovascular disease driven by chronic infection — a common clinical scenario where periodontal patients develop accelerated atherosclerosis. It highlights peptide receptors as versatile drug targets across multiple diseases.
Questions still open
- Would RC-3095 reduce atherosclerosis progression in patients with both periodontal disease and cardiovascular disease?
- Does the gastrin-releasing peptide pathway contribute to atherosclerosis driven by other bacterial infections or inflammation sources beyond P. gingivalis?
- Could RC-3095 be combined with standard periodontal and cardiovascular treatments for synergistic benefit?
Common questions
How does gum disease cause heart problems?
What is the gastrin-releasing peptide receptor and why block it?
Read the original research
Gastrin-releasing peptide receptor antagonist RC-3095 inhibits Porphyromonas gingivalis lipopolysaccharide-accelerated atherosclerosis by suppressing inflammatory responses in endothelial cells and macrophages.
Inflammation research : official journal of the European Histamine Research Society ... [et al.], 73(11), 1833-1846
Citation
Park, Hyun-Joo; Kim, Mi-Kyoung; Kim, Yeon; Kim, Hyung Joon; Park, Hae Ryoun; Bae, Soo-Kyung; Bae, Moon-Kyoung. (2024). Gastrin-releasing peptide receptor antagonist RC-3095 inhibits Porphyromonas gingivalis lipopolysaccharide-accelerated atherosclerosis by suppressing inflammatory responses in endothelial cells and macrophages.. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 73(11), 1833-1846. https://doi.org/10.1007/s00011-024-01934-0