Decreased release of
palmitic acid methyl ester (
PAME), a
vasodilator, from perivascular adipose tissue (PVAT) might contribute to
hypertension pathogenesis. However, the
PAME biosynthetic pathway remains unclear. In this study, we hypothesized that
PAME is biosynthesized from
palmitic acid (PA) via human
catechol-O-methyltransferase (COMT) catalysis and that decreased
PAME biosynthesis plays a role in
hypertension pathogenesis. We compared
PAME biosynthesis between age-matched normotensive Wistar Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHRs) and investigated the effects of
losartan treatment on
PAME biosynthesis. Computational molecular modeling indicated that PA binds well at the active site of COMT. Furthermore, in in vitro enzymatic assays in the presence of COMT and S-5'-adenosyl-L-methionine (
AdoMet), the stable
isotope [13C16]-PA was methylated to form [13C16]-
PAME in incubation medium or the
Krebs-Henseleit solution containing 3T3-L1 adipocytes or rat PVAT. The adipocytes and PVATs expressed membrane-bound (MB)-COMT and soluble (S)-COMT
proteins. [13C16]-PA methylation to form [13C16]-
PAME in 3T3-L1 adipocytes and rat PVAT was blocked by various COMT inhibitors, such as S-(5'-adenosyl)-L-homocysteine, adenosine-2',3'-dialdehyde, and
tolcapone. MB- and S-COMT levels in PVATs of established SHRs were significantly lower than those in PVATs of age-matched normotensive WKY rats, with decreased [13C16]-PA methylation to form [13C16]-
PAME. This decrease was reversed by
losartan, an
angiotensin II (Ang II) type 1 receptor antagonist. Therefore,
PAME biosynthesis in rat PVAT is dependent on
AdoMet, catalyzed by COMT, and decreased in SHRs, further supporting the role of PVAT/
PAME in
hypertension pathogenesis. Moreover, the
antihypertensive effect of
losartan might be due partly to its increased
PAME biosynthesis. SIGNIFICANCE STATEMENT:
PAME is a key PVAT-derived relaxing factor. We for the first time demonstrate that
PAME is synthesized through PA methylation via the S-5'-adenosyl-L-methionine-dependent COMT catalyzation pathway. Moreover, we confirmed PVAT dysfunction in the hypertensive state. COMT-dependent
PAME biosynthesis is involved in Ang II receptor type 1-mediated blood pressure regulation, as evidenced by the reversal of decreased
PAME biosynthesis in PVAT by
losartan in hypertensive rats. This finding might help in developing novel therapeutic or preventive strategies against
hypertension.