Circulation August 1, 2017 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run your weekly podcast summary and
backstage pass to the Journal and it's editors. I'm Dr. Carolyn
Lam associate editor from the National Heart Center and Duke
National University of Singapore.


                                               
Our feature paper this week provides important mechanistic
insights into oxidative stress and inflammation with aging. More
of that soon right after the summary of this week's journal.


                                               
The first paper contributes to our understanding of the genetic
and functional relevance of soluble guanylyl cyclase activity for
coronary artery disease. As background, a chromosomal locus at
4q32.1 has been associated with coronary artery disease risk with
genome wide significance. The locus encompasses GUCY1A3, which
encodes the alpha one subunit of the soluble guanylyl cyclase, a
key enzyme of the nitric oxide cyclic GMP signaling pathway.


                                               
In today's study from co-corresponding authors Dr. Kessler, and
Dr. Schunkert from Munich, Germany and colleagues the authors
showed that the GUCY1A3 locus has regulatory properties with the
risk allele leading to reduced expression of GUCY1A3. The lead
snip modulated finding of the transcription factor ZEB1 resulting
in reduced expression of GUCY1A3 in carriers of the risk allele.
As a consequence risk allele carriers demonstrated impaired
inhibition of vascular smooth muscle cell migration and platelet
aggregation after stimulation of the soluble guanylyl cyclase.


                                               
In summary, this study suggest that modulating soluble guanylyl
cyclase activity or inhibiting the effects of reduced expression
of GUCY1A3 may be promising therapeutic strategies for
individuals with the high risk alleles of GUCY1A3.


                                               
The next paper reports the outcome associations between adding a
radial arterial graft to single and bilateral internal thoracic
artery grafts in the arterial revascularization trial or ART. As
a reminder, ART was designed to compare survival after bilateral
internal thoracic artery over single left internal thoracic
artery bypass with about 20% also receiving a radial artery graft
instead of a saphenous vein graft.


                                               
In the current paper, first author Dr. Taggert from University of
Oxford and corresponding author Dr. Benedetto from University of
Bristol in the United Kingdom and colleagues showed that the
primary endpoint of ART which was a composite of myocardial
infarction, cardiovascular death and repeat revascularization at
five years was significantly lower in the radial artery group
when compared to the saphenous vein graft group. This association
was present when the radial artery graft was used to supplement
both the single internal thoracic artery as well as the bilateral
internal thoracic artery grafts.


                                               
In summary this post-hoc ART analysis showed that an additional
radial artery was associated with lower risk for mid-term major
adverse cardiac events when used to supplement single or
bilateral internal thoracic artery grafts.


                                               
The next study addresses the questions of whether intensive blood
pressure lowering beyond usual targets recommended by guidelines
would lead to more lowering of left ventricular hypertrophy in
patients with hypertension and whether reducing the risk of left
ventricular hypertrophy explains the reported cardiovascular
benefits of intensive blood pressure lowering.


                                               
To answer this question Dr. Soliman from Wake Forest School of
Medicine in North Carolina and colleagues studied the 8,164
participants with hypertension but no diabetes from the Systolic
Blood Pressure Intervention or SPRINT Trial. They showed that
among SPRINT participants without baseline left ventricular
hypertrophy, intensive blood pressure lowering was associated
with a 46% lower risk of developing left ventricular hypertrophy
compared to standard therapy. Similarly, among SPRINT
participants with baseline left ventricular hypertrophy blood
pressure lowering intensively was associated with a 66% greater
likelihood for regression or improvement of their left
ventricular hypertrophy. Furthermore, adjusting for left
ventricular hypertrophy as a time-varying covariate did not
substantially attenuate the effect of intensive blood pressure
therapy on cardiovascular disease events.


                                               
In summary these findings add further evidence of the benefits of
the intensive blood pressure lowering in patients with
hypertension and suggest that these benefits go beyond reducing
the hemodynamic stress on the cardiac structure. Further research
is needed to understand the mediating factors and mechanisms by
which intensive blood pressure lowering impacts the
cardiovascular system.


                                               
Well that wraps it up for our summaries, now for our feature
discussion.


                                               
We are going to talking about aging, oxidative stress and
inflammation today and really taking a deep dive into potential
mechanisms. I am so pleased to be here with the corresponding
author of our feature paper in this week's issue. And that is Dr.
Mustapha Rouis from INSERM University Paris six in France as well
associate editor from University of Rochester Dr. Charlie
Lowenstein.


                                               
Welcome gentlemen.


Dr. Charlie Lowenstein: Thank you for having us.


Dr. Mustapha Rouis:       Thank you
very much.


Dr. Carolyn
Lam:              
Mustapha, what inspired you to actually look at the Thioredoxin
system in looking at this aging question? What were your
hypotheses?


Dr. Mustapha Rouis:       Actually
our laboratories working on cardiovascular diseases for several
years. We have been trying to understand why oxidative stress and
inflammation increase with age despite the presence of a variety
of antioxidant proteins in the body. So among the antioxidant
proteins the Thioredoxin-1, isoform one which is a small
ubiquitous incytocylic protein called our attention because it's
a multi functional protein. It can exert an antioxidant role,
anti-inflammatory and anti-apositic role. So therefore we wanted
to know whether the increase in the oxidative stress and
inflammation with age is it due or at least in part to a
deficiency of Thioredoxin-1. If so is there increases due to a
decrease in protein synthesis or to increase in its degradation.


                                               
For this purpose we have constituted a cohort of young and old
subject, male and female. They want to focus on this particular
point because this is very important point it has not been easy
to achieve and we took a lot of time to sort and to keep only
subject meeting our criteria. Those who we wanted to enroll
consisting of people free from any history of diseases such as
cardiovascular diseases, diabetes, obesity, inflammation, any
kind of inflammation, cancer et cetera. In addition we wanted
subject without any risk factor for cardiovascular disease except
of course the age. No smoking, no hyperlipidemia and no taking
any medication.


                                               
This really very hard to achieve. Then once we have enough
subject we evaluate the Thioredoxin-1 using commercially
available very specific kit, ELISA kit and showed that the plasma
level of Thioredoxin-1 decreased significantly with age. Since it
has been described for several years that Thioredoxin-1 can be
cleaved at the C terminal level, the cleavage has been described
to be occur after lysine at position eight. This will generate a
truncated called Thioredoxin-80. We measured the plasma
concentration of Thioredoxin-80 in this sample, in this same
sample of the selected subject using an ELISA method developed in
our laboratory because there is no commercially kit for
Thioredoxin-80.


                                               
The result showed that Thioredoxin-80 increased with age
therefore the decrease in the plasma concentration of the full
length Thioredoxin-1 observed in the old, in the elderly is
probably due to an increase in its cleavage and not to a decrease
in its synthesis. Of note we observed an increase of the
expression and activity of two alpha secretases ADAM-10 and
ADAM-17 two enzyme responsible for the cleavage process in the
peripheral blood mononuclear cells of the old subject. Our
results consolidate our interpretation.


Dr. Carolyn
Lam:              
Wow, what a beautiful set of studies that included human samples
and then also included some very elegant mouse experiments. I
remember the excitement among the editors when we discussed this
paper. Charlie could you just share a little bit of what went on
when we looked at this?


Dr. Charlie Lowenstein: First I'd like to put this study into
context which is that oxidants increase during aging and it's
been known for a long time that animals that have high metabolic
rates have short life spans and one of the things that goes along
with high metabolic rate is a lot of radical production. And
since the 1950's there's been this theory, the free radical
theory of aging that radicals damage cells. And so the question
is, are radicals bad? What do they do in aging? And what defenses
do we have against them? So that's one of the contexts of this
article.


                                               
Secondly we also know that oxidants are associated with diseases.
Increased oxidants during cancer, during inflammatory diseases
and during atherosclerosis so that's why this study is important.
It's important for two reasons. First of all there's a theory
that as you age there's more radicals and radicals might actually
cause part of the problem in aging. Secondly radicals are also
associated with inflammatory diseases like atherosclerosis.


                                               
When the editors got this article, it was very exciting for
several reasons. First of all, the short form of Thioredoxin,
TRX-80 might explain why older people have more oxidative stress.
Secondly this short form TRX, TRX-80 might be a new bio-marker
for aging. And thirdly, the short form of Thioredoxin might help
us monitor different antioxidant therapies when people have too
many radicals. So for a number of important clinical reasons our
editors were very excited when we received this important
manuscript.


Dr. Carolyn
Lam:              
Mustapha, what are your next steps when it comes to this?


Dr. Mustapha Rouis:       Well
several studies have shown that Thioredoxin-1 can reduce
inflammation and can protect the body against several pathologies
which has an increased interest in its use for therapeutic
purpose. However its cleavage in the generation of the
Thioredoxin-80, limited research work in this direction so I just
remember you that the Thioredoxin-80, the truncated form in
contrast to the full length Thioredoxin-1 exerts a pro-oxidant,
pro-inflammatory angiogenic and carcinogenic effect. So
nevertheless in order to counter these difficulties we plan to
synthesize some Thioredoxin limited peptides such as catalytic
site containing peptides and these peptide used it in therapy
could show significant biologic activity. This peptide could lose
constitute maybe an alternative to the full length Thioredoxin.


Dr. Carolyn
Lam:              
Wow, that is exciting. Charlie, what do think is the take home
message for clinicians listening to this?


Dr. Charlie Lowenstein: Scientists and clinicians all agree that
an excess of radicals is bad. But there's an antioxidant paradox
which is when patients take antioxidants like vitamin E, those
antioxidants don't help. In a large clinical trial suggesting
that vitamin E and other antioxidants don't help. So the question
is, maybe antioxidant therapy helps some patients but doesn't
help others. One of the interesting aspects of this study that
maybe the presence or absence of TRX-80 might determine whether
antioxidant therapies will help. Furthermore, maybe TRX-80 levels
might be able to guide patients as to whether or not they should
take antioxidant therapy. There are many important aspects of
this study that point toward future studies.


Dr. Mustapha Rouis:       We
thought about inhibiting the ADAM-10, ADAM-17 alpha secretase
enzyme to prevent the cleavage process and I know that many drug
companies are trying to find the specific inhibitors but the
problem is these two enzyme are benefit in brain for enzymatic
disease. So waiting to have a specific inhibitor for this enzyme
that do not cross the hematoencephalic barrier to use it in
humans but until that we may be the use or conceive the peptides
it's better approach.


Dr. Carolyn
Lam:              
I'm just loving this discussion because it's really bringing out
a lot more to this paper than I realized as a clinician. Charlie
could you end by just saying a few words about how we look at
basic science papers in Circulation and the importance of the
clinical translation element that we keep saying is our primary
focus.


Dr. Charlie Lowenstein: Circulation is a great journal that
covers important clinical topics. There's a lot of basic science
that underlies some of these clinical topics so whenever we get a
paper that gives us insight into a disease or reveals a new
therapy and it's at the basic level we look very carefully at it.
We want to know, will it help our readers understand something
about the clinical process, clinical disease, diagnostics
[inaudible 00:16:00] So when we get a paper we look at it very
carefully and emphasize it has to be a basic paper that reveals a
mechanism that's important to clinicians. That clinicians can
understand and appreciate and gain insight about what's going on
with their patients. I'm both a clinician and a scientist, I am
charged with trying to figure out what basic concepts are
relevant to our clinical audience.


Dr. Carolyn
Lam:              
Thank you Mustapha, thank you Charlie and thank you listeners for
tuning in this week. Don't forget to tune in again next week.