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Kyoto Prefectural University of Medicine Kyoto, Japan
Correspondence to: Ken-ichiro Inoue, MD, First Department of Internal Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto-city, 602-8858, Kyoto, Japan; e-mail: keni{at}kk.ii4u.or.jp
To the Editor:
We read with interest the recent article by Houghton and
colleagues (September 2000),1
which indicated an
improvement in coronary resistance artery function in
hypercholesterolemic patients after treatment with pravastatin. After
reading the article, we would like to know whether such endothelial
function is improved by treatment with other types of lipid-lowering
agents, such as bezafibrate and clofibrate. Bezafibrate and clofibrate
are recognized not only as hypolipidemic drugs, but as pharmacologic
ligands of peroxisome proliferator-activated receptor 
(PPAR-), one of the ligand-activated nuclear receptor
transcriptional factors.2
Inoue et al3
demonstrated the expression of PPAR- in human vascular endothelial
cells by reverse transcriptase-polymerase chain reaction. They also
demonstrated the increased expression of PPAR- in these cells after
exposure to bezafibrate, suggesting that PPAR- in endothelial cells
plays a regulatory role in the pathogenesis of hyperlipidemia and
atherosclerosis, and also in the processes of inflammation and
coagulation. Another study4
reported that inflammatory
activation of aortic smooth muscle cells, which is a hallmark of
atherosclerosis, is inhibited by the activation of PPAR- by these
fibrates. In addition, the activation of PPAR- by these fibrates
leads to the induction of apolipoprotein (apo)-AI and apo-AII
expression in hepatocytes, resulting in an increase in circulating
high-density lipoprotein cholesterol.5
Therefore,
further study of resistance artery endothelial function in relation to
such fibrates might result in more interesting data.
References
in humans. Diabetes 46,1319-1327[Abstract]
(PPAR ) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun 246,370-374[CrossRef][ISI][Medline]
but not PPAR
activators. Nature 393,790-793[CrossRef][Medline]
Albany Medical College Albany, NY
Correspondence to: Jan Laws Houghton, MD, Division of Cardiology, A-44, Albany Medical College, Albany, NY 12208; e-mail: Houghtj{at}mail.amc.edu
To the Editor:
Inoue and colleagues are correct in bringing to attention the possible role of fibrate drugs, a different class of lipid-lowering agent than that employed in our study (September 2000),1 for use in treatment of endothelial dysfunction. Seiler et al2 showed that cholesterol-lowering therapy with benzafibrate, over a 7-month period, resulted in improved exercise-induced vasomotion of angiographically normal and previously dilated stenotic coronary arteries.
Evans et al3 recently reported that after 3 months of treatment with ciprofibrate, improvement was demonstrated in fasting and postprandial brachial artery endothelial function among subjects with type 2 diabetes mellitus. The comments of Inoue et al regarding the vascular biology of fibrate drugs are topical. Evidence mounts that not only cholesterol-lowering but nonlipid effects of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor drugs are important elements in the ultimate clinical benefit. For example, one important collateral effect of these agents, which was initially unexpected, is the apparent reduction of endothelial inflammation. Ridker et al4 found, in the Air Force/Texas Coronary Atherosclerosis Prevention Study, that treatment with lovastatin among subjects with average low-density lipoprotein (LDL) cholesterol levels independently lowered levels of C-reactive protein (CRP), the prototypic marker of vascular inflammation. Retrospective analysis showed that this translated into an improved cardiovascular event rate in subjects with elevated CRP levels even among those with low LDL cholesterol levels. A number of large randomized clinical trials5 6 have shown clinical benefits in patients after treatment with HMG-CoA reductase inhibitors resulting in significant reductions in myocardial infarction, stroke, and death during follow-up. The benefits have been conjectured to be out of proportion to the observed LDL reduction.7 This further supports the notion that lipid-lowering agents have other actions that independently lead to the repair of endothelial dysfunction. Ultimately, expanded indications for the use of lipid-lowering agents are likely in both the primary and secondary prevention of clinically significant coronary artery disease. In the future, the selection of lipid-lowering agents may be complexly dictated by factors such as the degree of vascular inflammation and the presence of postprandial lipemia in addition to the classical quantitative assessment of high-density and LDL cholesterol and triglyceride levels.
References
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