TY - JOUR
T1 - Paraoxonase1 deficiency in mice is associated with hypotension and increased levels of 5,6-epoxyeicosatrienoic acid
AU - Gamliel-Lazarovich, Aviva
AU - Abassi, Zaid
AU - Khatib, Soliman
AU - Tavori, Hagai
AU - Vaya, Jacob
AU - Aviram, Michael
AU - Keidar, Shlomo
PY - 2012/5
Y1 - 2012/5
N2 - Aim: Serum paraoxonase 1 (PON1) is an HDL-associated lipolactonase and its association with hypertension is controversial. We studied the possible role of PON1 in blood pressure (BP) regulation, by using PON1 knockout (PON1KO) mice. Methods and results: Both, systolic and diastolic BPs were lower in PON1KO compared to WT mice. Hypotension detected in PON1KO is probably neither related to nitric oxide/guanylate cyclase-mediated vasodilation nor to angiotensin II or aldosterone-mediated vasoconstriction. Surprisingly, when challenged by high-salt diet, BP was further reduced in PON1KO mice. The later, pointed to a possible involvement of transient receptor potential vanilloid 4 (TRPV4), and indeed, administration of ruthenium red, a TRPV4 blocker, resulted in a sharp rise in BP. The protein levels of TRPV4 in kidneys of PON1KO were not higher than in WT. However, the renal level of 5,6-epoxyeicosatrienoic acid (5,6-EET), a TRPV4 specific agonist, was significantly higher in PON1KO compared with WT mice. 5,6-EET levels were further elevated under high-salt diet or administration of arachidonic acid. Injection of inhibitor of CYP450 epoxygenase resulted in increased BP in PON1KO mice. Injection of recombinant human PON1 resulted in elevation of BP and a concomitant reduction in renal content of 5,6-EET. PON1, in vitro, metabolized 5,6-EET, but not other EETs, to its corresponding diol. Vasodilation, blocked by excess of dietary K + but not reversed by depletion of cellular Ca 2+ stores, point to endothelial-derived hyperpolarization-like response. Conclusion: The present study shows causal, direct relationship between PON1 and blood pressure which is mediated, at least in part, by the regulation of 5,6-EET.
AB - Aim: Serum paraoxonase 1 (PON1) is an HDL-associated lipolactonase and its association with hypertension is controversial. We studied the possible role of PON1 in blood pressure (BP) regulation, by using PON1 knockout (PON1KO) mice. Methods and results: Both, systolic and diastolic BPs were lower in PON1KO compared to WT mice. Hypotension detected in PON1KO is probably neither related to nitric oxide/guanylate cyclase-mediated vasodilation nor to angiotensin II or aldosterone-mediated vasoconstriction. Surprisingly, when challenged by high-salt diet, BP was further reduced in PON1KO mice. The later, pointed to a possible involvement of transient receptor potential vanilloid 4 (TRPV4), and indeed, administration of ruthenium red, a TRPV4 blocker, resulted in a sharp rise in BP. The protein levels of TRPV4 in kidneys of PON1KO were not higher than in WT. However, the renal level of 5,6-epoxyeicosatrienoic acid (5,6-EET), a TRPV4 specific agonist, was significantly higher in PON1KO compared with WT mice. 5,6-EET levels were further elevated under high-salt diet or administration of arachidonic acid. Injection of inhibitor of CYP450 epoxygenase resulted in increased BP in PON1KO mice. Injection of recombinant human PON1 resulted in elevation of BP and a concomitant reduction in renal content of 5,6-EET. PON1, in vitro, metabolized 5,6-EET, but not other EETs, to its corresponding diol. Vasodilation, blocked by excess of dietary K + but not reversed by depletion of cellular Ca 2+ stores, point to endothelial-derived hyperpolarization-like response. Conclusion: The present study shows causal, direct relationship between PON1 and blood pressure which is mediated, at least in part, by the regulation of 5,6-EET.
KW - 5,6-EET
KW - Hypertension
KW - Nitric oxide
KW - PON1
KW - RAAS
KW - TRPV4
UR - http://www.scopus.com/inward/record.url?scp=84859852834&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859852834&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2012.01.047
DO - 10.1016/j.atherosclerosis.2012.01.047
M3 - Article
C2 - 22365750
AN - SCOPUS:84859852834
SN - 0021-9150
VL - 222
SP - 92
EP - 98
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -