Porphyromonas gingivalis
(P.g), a major causative agent of periodontitis, has been linked to atherosclerosis, a chronic inflammatory vascular disease. Recent studies have suggested a link between periodontitis and arterial stiffness, a risk factor for atherosclerosis. However, the mechanisms by which P.g infection contributes to atherogenesis remain elusive. The formation of lipid‐laden macrophage “foam cells” is critically important to development and progression of atherosclerosis. We have obtained evidence that
TRPV
4 (transient receptor potential channel of the vanilloid subfamily 4), a mechanosensitive channel, is a regulator of macrophage foam cell formation both in response to P.g‐derived lipopolysaccharide (Pg
LPS
) or to an increase in matrix stiffness. Importantly, we found that
TRPV
4 activity (Ca
2+
influx) was increased in response to Pg
LPS
. Genetic deletion or chemical antagonism of
TRPV
4 channels blocked Pg
LPS
‐triggered exacerbation of oxidized
LDL
(ox
LDL
)‐mediated foam cell formation. Mechanistically, we found that (1) T
RPV
4 regulated ox
LDL
uptake but not its cell surface binding in macrophages; (2) reduced foam cell formation in
TRPV
4 null cells was independent of expression of
CD
36, a predominant receptor for ox
LDL
, and (3) co‐localization of
TRPV
4 and
CD
36 on the macrophage plasma membrane was sensitive to the increased level of matrix stiffness occurring in the presence of Pg
LPS
. Altogether, our results suggest that
TRPV
4 channels play an essential role in P.g‐induced exacerbation of macrophage foam cell generation through a mechanism that modulates uptake of ox
LDL
.
Although P. gingivalis, a predominant causative agent of periodontitis, has been linked to lipidladen macrophage foam cell formation, a critical process in atherogenesis, the mechanism remains elusive. Emerging data support a role for both a biochemical factor, e.g., lipopolysaccharides (LPS), and a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family, and a known mechanosensor, is the likely mediator of P. gingivalis lipopolysaccharide (PgLPS)‐induced exacerbation of oxidized low‐density lipoprotein (oxLDL)‐mediated macrophage foam cell formation. Specifically, we found that: i) genetic deletion of TRPV4 or antagonism of its function by a chemical inhibitor blocked PgLPS‐induced exacerbation of oxLDL‐induced macrophage foam cell formation; ii) macrophage TRPV4 activity was increased in response to both PgLPS and pathophysiological range matrix stiffness, and iii) TRPV4 deficiency blocked PgLPS‐induced exacerbation of matrix stiffness‐induced macrophage foam cell formation. Mechanistically, we show that TRPV4 regulates PgLPS‐induced oxLDL uptake but not its cell surface binding in macrophages. Altogether, these findings identify a critical role for TRPV4 in regulating PgLPS‐induced exacerbation of macrophage foam cell formation by modulating uptake of oxLDL.Support or Funding InformationAHA (13SDG17310007), Startup grant from University of Maryland, NIH (1R01EB024556‐01), and NSF (CMMI‐1662776) grants to SOR.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
P. gingivalis, a predominant causative agent of periodontitis, has been linked to lipid‐laden macrophage foam cell formation, a critical process in atherogenesis. Emerging data support a role for both a biochemical factor, e.g., lipopolysaccharides (LPS), and a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function and atherogenesis. We have obtained evidence that TRPV4, a mechanosensitive channel of the transient receptor potential vanilloid family, is the likely mediator of P. gingivalis lipopolysaccharide (PgLPS)‐induced exacerbation of oxidized low‐density lipoprotein (oxLDL)‐mediated macrophage foam cell formation. Specifically, we found that: i) genetic deletion of TRPV4 or antagonism of its function by a chemical inhibitor blocked PgLPS‐induced exacerbation of oxLDL‐induced macrophage foam cell formation; ii) macrophage TRPV4 activity was increased in response to both PgLPS and pathophysiological range matrix stiffness, and iii) TRPV4 deficiency blocked PgLPS‐induced exacerbation of matrix stiffness‐induced macrophage foam cell formation. Mechanistically, we show that TRPV4 regulates PgLPS‐induced oxLDL uptake but not its cell surface binding in macrophages. Altogether, these findings identify a critical role for TRPV4 in regulating PgLPS‐induced exacerbation of macrophage foam cell formation by modulating uptake of oxLDL.Support or Funding InformationAHA (13SDG17310007), Startup grant from University of Maryland, NIH (1R01EB024556‐01), and NSF (CMMI‐1662776) grants to Shaik RahamanThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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