Limits...
Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia.

Poulain L, Richard V, Lévy P, Dematteis M, Arnaud C - Mediators Inflamm. (2015)

Bottom Line: The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications.As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

View Article: PubMed Central - PubMed

Affiliation: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.

ABSTRACT

Objective: Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.

Methods: Lean adult male TLR4-deficient (TLR4(-/-)) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta.

Results: IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion.

Conclusion: IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

No MeSH data available.


Related in: MedlinePlus

TLR4 signaling is involved in IH-induced vascular remodeling. Morphometric and inflammatory remodeling of aorta was assessed in C57BL/6 and TLR4−/− mice exposed to 4 weeks of intermittent hypoxia (IH) or normoxia (N). (a) Aortic intima-media thickness quantification, (b) representative photographs of aorta remodeling (wall thickness represented by white double-headed arrows), (c) quantification of activated NFκB (NFκB-p50 activity) in aorta (n = 8–11 per group). (d) Plasma levels of total cholesterol in C57BL/6 and TLR4−/− mice exposed to 4 weeks of IH or N, n = 12–16 per group. *P < 0.05 IH/C57BL/6 versus N/C57BL/6.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4383499&req=5

fig3: TLR4 signaling is involved in IH-induced vascular remodeling. Morphometric and inflammatory remodeling of aorta was assessed in C57BL/6 and TLR4−/− mice exposed to 4 weeks of intermittent hypoxia (IH) or normoxia (N). (a) Aortic intima-media thickness quantification, (b) representative photographs of aorta remodeling (wall thickness represented by white double-headed arrows), (c) quantification of activated NFκB (NFκB-p50 activity) in aorta (n = 8–11 per group). (d) Plasma levels of total cholesterol in C57BL/6 and TLR4−/− mice exposed to 4 weeks of IH or N, n = 12–16 per group. *P < 0.05 IH/C57BL/6 versus N/C57BL/6.

Mentions: Hypoxic C57BL/6 mice had morphological and functional alterations of their aorta, as they exhibited larger intima-media thickness (Figures 3(a) and 3(b)) and higher NFκB-p50 activity (Figure 3(c)). These alterations were not observed in hypoxic TLR4−/− mice (Figures 3(a), 3(b), and 3(c)). Plasma levels of total cholesterol were not different between the 4 experimental groups (Figure 3(d)).


Toll-like receptor-4 mediated inflammation is involved in the cardiometabolic alterations induced by intermittent hypoxia.

Poulain L, Richard V, Lévy P, Dematteis M, Arnaud C - Mediators Inflamm. (2015)

TLR4 signaling is involved in IH-induced vascular remodeling. Morphometric and inflammatory remodeling of aorta was assessed in C57BL/6 and TLR4−/− mice exposed to 4 weeks of intermittent hypoxia (IH) or normoxia (N). (a) Aortic intima-media thickness quantification, (b) representative photographs of aorta remodeling (wall thickness represented by white double-headed arrows), (c) quantification of activated NFκB (NFκB-p50 activity) in aorta (n = 8–11 per group). (d) Plasma levels of total cholesterol in C57BL/6 and TLR4−/− mice exposed to 4 weeks of IH or N, n = 12–16 per group. *P < 0.05 IH/C57BL/6 versus N/C57BL/6.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383499&req=5

fig3: TLR4 signaling is involved in IH-induced vascular remodeling. Morphometric and inflammatory remodeling of aorta was assessed in C57BL/6 and TLR4−/− mice exposed to 4 weeks of intermittent hypoxia (IH) or normoxia (N). (a) Aortic intima-media thickness quantification, (b) representative photographs of aorta remodeling (wall thickness represented by white double-headed arrows), (c) quantification of activated NFκB (NFκB-p50 activity) in aorta (n = 8–11 per group). (d) Plasma levels of total cholesterol in C57BL/6 and TLR4−/− mice exposed to 4 weeks of IH or N, n = 12–16 per group. *P < 0.05 IH/C57BL/6 versus N/C57BL/6.
Mentions: Hypoxic C57BL/6 mice had morphological and functional alterations of their aorta, as they exhibited larger intima-media thickness (Figures 3(a) and 3(b)) and higher NFκB-p50 activity (Figure 3(c)). These alterations were not observed in hypoxic TLR4−/− mice (Figures 3(a), 3(b), and 3(c)). Plasma levels of total cholesterol were not different between the 4 experimental groups (Figure 3(d)).

Bottom Line: The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications.As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

View Article: PubMed Central - PubMed

Affiliation: Université Grenoble Alpes, Laboratoire HP2, 38042 Grenoble, France ; INSERM U1042, 38042 Grenoble, France.

ABSTRACT

Objective: Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.

Methods: Lean adult male TLR4-deficient (TLR4(-/-)) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta.

Results: IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion.

Conclusion: IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

No MeSH data available.


Related in: MedlinePlus