Nicotinic acid activates the capsaicin receptor TRPV1: Potential mechanism for cutaneous flushing

Linlin Ma, Bo Hyun Lee, Rongrong Mao, Anping Cai, Yunfang Jia, Heather Clifton, Saul Schaefer, Lin Xu, Jie Zheng

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective-Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results-We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1-/- knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions-Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.

Original languageEnglish (US)
Pages (from-to)1272-1280
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number6
DOIs
StatePublished - 2014

Fingerprint

TRPV Cation Channels
Niacin
Skin
Capsaicin
Vasodilation
Niacinamide
Optical Imaging
Dyslipidemias
Knockout Mice
Compliance
Cardiovascular Diseases
Hot Temperature
Ligands

Keywords

  • cardiovascular diseases
  • ion channels
  • lipoproteins
  • vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Nicotinic acid activates the capsaicin receptor TRPV1 : Potential mechanism for cutaneous flushing. / Ma, Linlin; Lee, Bo Hyun; Mao, Rongrong; Cai, Anping; Jia, Yunfang; Clifton, Heather; Schaefer, Saul; Xu, Lin; Zheng, Jie.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 34, No. 6, 2014, p. 1272-1280.

Research output: Contribution to journalArticle

Ma, Linlin ; Lee, Bo Hyun ; Mao, Rongrong ; Cai, Anping ; Jia, Yunfang ; Clifton, Heather ; Schaefer, Saul ; Xu, Lin ; Zheng, Jie. / Nicotinic acid activates the capsaicin receptor TRPV1 : Potential mechanism for cutaneous flushing. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2014 ; Vol. 34, No. 6. pp. 1272-1280.
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abstract = "Objective-Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results-We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1-/- knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions-Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.",
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T2 - Potential mechanism for cutaneous flushing

AU - Ma, Linlin

AU - Lee, Bo Hyun

AU - Mao, Rongrong

AU - Cai, Anping

AU - Jia, Yunfang

AU - Clifton, Heather

AU - Schaefer, Saul

AU - Xu, Lin

AU - Zheng, Jie

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N2 - Objective-Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results-We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1-/- knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions-Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.

AB - Objective-Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. Approach and Results-We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1-/- knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. Conclusions-Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.

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