Increased arachidonic acid-induced thromboxane generation impairs skeletal muscle arteriolar dilation with genetic dyslipidemia.
OBJECTIVE
The aim of this study was to determine if arachidonic acid (AA)-induced skeletal muscle arteriolar dilation is altered with hypercholesterolemia in ApoE and low-density lipoprotein receptor (LDLR) gene deletion mice fed a normal diet. This study also determined contributors to altered AA-induced dilation between dyslipidemic mice and controls, C57/Bl/6J (C57).


METHODS
Gracilis muscle arterioles were isolated, with mechanical responses assessed following a challenge with AA under control conditions and after elements of AA metabolism pathways were inhibited. Conduit arteries from each strain were used to assess AA-induced production of PGI(2) and TxA(2).


RESULTS
Arterioles from ApoE and LDLR exhibited a blunted dilation to AA versus C57. While responses were cyclo-oxygenase-dependent in all strains, inhibition of thromboxane synthase or blockade of PGH(2)/TxA(2) receptors improved dilation in ApoE and LDLR only. AA-induced generation of PGI(2) was comparable across strains, although TxA(2) generation was increased in ApoE and LDLR. Arteriolar reactivity to PGI(2) and TxA(2) was comparable across strains. Treatment with TEMPOL improved dilation and reduced TxA(2) production with AA in ApoE and LDLR.


CONCLUSIONS
These results suggest that AA-induced arteriolar dilation is constrained in ApoE and LDLR via an increased production of TxA(2). While partially due to elevated oxidant stress, additional mechanisms contribute that are independent of acute alterations in oxidant tone.
Goodwill
Adam G
AG
Department of Physiology and Pharmacology, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26505, USA.
Stapleton
Phoebe A
PA
James
Milinda E
ME
D'Audiffret
Alexandre C
AC
Frisbee
Jefferson C
JC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D001160:Arterioles / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism*; D044262:Prostaglandin H2 / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D013113:Spin Labels; D013928:Thromboxane A2 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D000975:Antioxidants; D001057:Apolipoproteins E; D003497:Cyclic N-Oxides; D011973:Receptors, LDL; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013113:Spin Labels; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D013928:Thromboxane A2; C001803:tempol