Paraoxonase1 deficiency in mice is associated with hypotension and increased levels of 5,6-epoxyeicosatrienoic acid.

Aviva Gamliel-Lazarovich, Zaid Abassi, Soliman Khatib, Hagai Tavori, Jacob Vaya, Michael Aviram, Shlomo Keidar

Lipid Research Laboratory, The Rappaport Family Institute for Research in the Medical Sciences, Rappaport Faculty of Medicine, Technion and Rambam Medical Center, Haifa, Israel.

Atherosclerosis 2012 May

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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. 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. 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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Citation

Aviva Gamliel-Lazarovich, Zaid Abassi, Soliman Khatib, Hagai Tavori, Jacob Vaya, Michael Aviram, Shlomo Keidar. Paraoxonase1 deficiency in mice is associated with hypotension and increased levels of 5,6-epoxyeicosatrienoic acid. Atherosclerosis. 2012 May;222(1):92-8