X-Message-Number: 27838
Date: Tue, 11 Apr 2006 18:54:14 -0700 (PDT)
From: Doug Skrecky <>
Subject: antioxidants a bust, HO-1 protects against atherosclerosis

[It seems to be human to over-estimate ones own knowledge. The scientific
community years ago bought into the free radical theory of aging, hook,
line, sinker, and fishing reel. Although that theory has since been
discredited, after a number of negative intervention studies on human
mortality using antioxidants, it is only now that the true picture of what
really drives human mortality is being discovered...]

Free-radical Busting Antioxidants Might Not Promote Healthy Hearts
  Antioxidants, such as beta-carotene and Vitamin E, have been touted for
their ability to protect against heart disease. This protective effect is
attributed to their ability to prevent the oxidation of bad cholesterol
by free radicals -- a process thought to contribute to the build-up of
disease-causing fatty deposits on artery walls. But a new study,
published online on April 10 in The Journal of Experimental Medicine,
suggests that the heart-healthy effect of one antioxidant has little to
do with cholesterol oxidation.
  A group of researchers at the University of New South Wales in
Australia, led by Roland Stocker, studied a cholesterol-lowering drug
called Probucol (Lorelco) in laboratory rodents with vascular
disease. Probucol reduces the risk of heart disease in humans, but is no
longer prescribed in the US and Australia because of adverse side
effects: a tendency to lower good cholesterol along with the bad and the
potential to induce an irregular heartbeat. Probucol is still available
in Canada and Europe.
  In their new study, Stocker and his colleagues show that the protective
effect of probucol has nothing to do with its ability to scavenge oxygen
free radicals, as the free radical-busting part of the drug alone was
ineffective in protecting animals against heart disease. Instead, a
different part of the probucol molecule was doing the beneficial work.
In fact, contrary to widely accepted opinion, the group found no
relationship between the levels of oxidized cholesterol in blood vessels
and the severity of heart disease. This might help explain the
disappointing results of clinical trials with other free
radical-scavenging antioxidants, such as Vitamin E, which have shown no
protective effect against heart disease in humans.
  The protective effect of these compounds depended on the induction of a
cellular enzyme called heme oxygenase-1 (HO-1). HO-1 is known to protect
against atherosclerosis in animal models, although the mechanism is not
completely clear. Not surprisingly, HO-1 was not induced by Vitamin E.
  Drugs closely related to probucol that contain the protective part of
the drug were just as protective as the original drug. If these probucol
relatives -- one of which is now being tested in humans -- are free of
side effects, they may provide a more effective alternative to current
therapies.

Published online 10 April 2006. doi:10.1084/jem.20052321
Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway
that is independent of free radical scavenging
  Oxidative stress is implicated in atherogenesis, yet most clinical
trials with antioxidants, particularly vitamin E, have failed to protect
against atherosclerotic diseases. A striking exception is probucol, which
retards atherosclerosis in carotid arteries and restenosis of coronary
arteries after angioplasty. Because probucol has in vitro
cellular-protective effects independent of inhibiting lipid oxidation, we
investigated the mode of action of probucol in vivo. We used three models
of vascular disease: apolipoprotein E-deficient mice, a model of
atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and
carotid injury in obese Zucker rats, a model of type 2
diabetes. Unexpectedly, we observed that the phenol moieties of probucol
were insufficient, whereas its sulphur atoms were required for
protection. Probucol and its sulphur-containing metabolite, but not a
sulphur-free phenolic analogue, protected via cell-specific effects on
inhibiting macrophage accumulation, stimulating reendothelialization, and
inhibiting vascular smooth muscle cell proliferation. These processes
were mediated via induction of heme oxygenase-1 (HO-1), an activity not
shared by vitamin E. Our findings identify HO-1 as the molecular target of
probucol. They indicate 2-electron rather than radical
(1-electron) oxidants as important contributors to atherogenesis, and
point to novel lead compounds for therapeutic intervention against
atherosclerotic diseases.

Histol Histopathol. 2006 Jun;21(6):679-85.
Heme oxygenase-1 and cardiovascular disease.
  Heme oxygenase (HO)-1 is the inducible isoform of the first and
rate-controlling enzyme of heme degradation. HO-1 is up-regulated by a
host of oxidative stress stimuli and has potent cytoprotective and
anti-inflammatory functions via decreasing tissue levels of the
prooxidant heme along with production of bilirubin and the signaling gas
carbon monoxide. This review deals with recent findings that highlight
the emerging significance of HO-1 in cardiovascular disease. Evidence is
presented on how heme and various oxidative stress stimuli may cause
endothelial cell dysfunction and how HO-1 may counteract the detrimental
effects of oxidative stress in the endothelium. Recent advances in the
understanding of the role of endothelial HO-1 for the regulation of the
inflammatory response are summarized, including the modulation of
leukocyte recruitment and transmigration through the endothelial
barrier. Furthermore, experimental evidence from various cell culture and
animal models is discussed which suggests an association of HO-1 with the
complex sequence of events that cause atherosclerosis. In the second part
of the review we present potential strategies that apply HO-1 as a
therapeutic target in the treatment of cardiovascular disease. Specific
inducers of HO-activity which may ultimately lead to the development of
clinically relevant pharmacological applications are introduced.

[Effects on HO-1 may explain the benefits of some popular drugs.]

Biochem Biophys Res Commun. 2006 May 12;343(3):738-44. Epub 2006 Mar 20.
Tissue-specific effects of statins on the expression of heme oxygenase-1
in vivo.
  Heme oxygenase-1 (HO-1) plays a central role in antioxidant and
anti-inflammatory actions, which may be mediated through its formation of
biliverdin/bilirubin and carbon monoxide. HMG-CoA reductase inhibitors
(statins) induce in vitro HO-1 expression and are reported to have
pleiotropic benefits that reduce oxidative stress in the vasculature. We
characterized the effects of statins on in vivo HO-1 expression in
various extravascular tissues: liver, lung, brain, and heart. Adult mice
were orally administered simvastatin, lovastatin, atorvastatin, or
rosuvastatin. HO activity significantly increased in a statin- and
tissue-specific manner, with all statins increasing heart and lung
activity within 24h. Significant elevations of HO-1 protein and mRNA were
also observed in heart and lung after atorvastatin treatment. We conclude
that in vivo HO-1 induction is statin- and tissue-specific. Through this
pathway, statins may confer antioxidant and anti-inflammatory actions in
the vasculature and extravascular systems.

[...and some not-so-popular OTC supplements as well.]

Forsch Komplementarmed. 2006 Feb;13 Suppl 1:13-7. Epub 2006 Feb 17.
Anti-inflammatory mechanisms of the tibetan herbal preparation padma 28
in the vessel wall.
  BACKGROUND: The Tibetan herbal preparation Padma 28 has been shown to
act as an anti-atherosclerotic agent in advanced peripheral arterial
occlusive disease. We tested the effect of aqueous Padma 28 extracts on
both the C reactive protein (CRP) induced expression of the
pro-inflammatory cell adhesion molecule E-selectin and the
anti-atherosclerotic protective enzyme heme oxygenase- 1 (HO-1) in human
aortic endothelial cells. METHODS AND RESULTS: According to FACS
analysis, quantitative RT-PCR and Western blot, CRP-induced E-selectin
expression was completely prevented by aqueous Padma 28
extracts. Additionally, Padma 28 mediated an up to 60-fold upregulation
of HO-1 mRNA as measured by quantitative RT-PCR. This upregulation could
also be demonstrated on the protein level. CONCLUSION: Aqueous extracts
of the Tibetan herbal preparation Padma 28 inhibit CRP-induced expression
of the inflammatory cell adhesion molecule E-selectin and lead to
upregulation of the vascular protective enzyme HO-1 in human aortic
endothelial cells. These properties may be responsible for its
anti-atherosclerotic effects in peripheral arterial occlusive disease.

Atherosclerosis. 2006 Apr 3; [Epub ahead of print]
Treating intermittent claudication with Tibetan medicine Padma 28: Does
it work?
  Herbal drugs are being increasingly used in medical practice, often
without appropriate scrutiny of their safety and efficacy. The medicinal
product Padma 28 is a fixed combination with Tibetan origin, used in
Europe since the 1960s for the symptomatic treatment of circulatory
disorders, including those of peripheral arterial occlusive disease
(PAOD). We have conducted an analysis of all available data on this
herbal drug from published literature as well as from original data we
obtained from contacting the authors of published papers, reports and the
manufacturer. A total of 19 trials have reported on 2084 patients to date,
444 of whom were in six controlled clinical studies on PAOD. A
meta-analysis of five trials showed Padma 28 to increase walking distance
by >100m in 18.2% of the patients with verum, versus 2.1% with placebo
(P<0.001; odds ratio: 10 [95% CI 3.03, 33.33]; RR: 0.12; number needed to
treat=6.2). The safety profile appears to be favourable. Available
evidence shows that Padma 28 provides significant relief from
PAOD-related symptoms (i.e. walking distance), probably of the same order
of magnitude as other employed medications. However, larger confirmatory
RCTs are desirable.

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