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From: Kofi on 15 Apr 2008 23:08
For quite a while now, mercury accumulation has been observed in the
heart muscle of patients with cardiomyopathy (heart failure). I believe
we finally have a good explanation for why this occurs. It turns out
that heart muscle contraction is directly regulated by histone
acetylation. HDAC inhibitors sensitize the heart muscle to calcium.
Metallothionein, the body's chief mercury chelator, is also under
epigenetic control by histones [PMID 16329111]. Loss of histone
acetylation in heart muscle would explain both the heart failure and the
mercury accumulation.

This new insight into heart muscle contraction also indicates potential
complications by HDAC inhibitors like sodium butyrate, particularly when
coupled with vitamin D3 - a potent combination for limiting tumor growth
and for treating autoimmunity and possibly organ rejection. Vitamin D3
elevates calcium and butyrate sensitizes the heart muscle to that extra
calcium. It also stands to reason that in autoimmune conditions where
vitamin D3 is low and butyrate production is knocked out in the gut,
this could have implications for heart function. Low blood flow from
heart failure itself has been known to produce leaky gut-style digestive
problems.

<http://www.sciencedaily.com/releases/2008/04/080409124859.htm>

Process Behind Heart Muscle Contraction Uncovered

ScienceDaily (Apr. 12, 2008) � Researchers from the University of
Pittsburgh and the University of Chicago were able to control heart
muscle function in a new way after discovering the previously unknown
role of two enzymes in heart muscle contraction, as detailed in the
April 11 cover story of the Journal of Biological Chemistry. Although in
the early stages, the research provides fresh knowledge of how heart
muscle functions and also holds early potential as a treatment for
various heart diseases�including congestive heart failure�that is
possibly less taxing on the heart than current regimens.

Experiments on slivers of heart muscle revealed that heart muscle
contractions can be regulated by the enzymes histone acetyltransferases
(HATs) and histone deacetylases (HDACs), explained Pitt professor
Sanjeev Shroff, the Gerald McGinnis Chair of Bioengineering in the
Swanson School of Engineering. Shroff and Pitt research associate
Stephen Smith collaborated with Mahesh Gupta, an associate professor of
surgery at the University of Chicago, and his research associate Sadhana
Samant.

The team found that HATs and HDACs influence acetylation of certain
heart muscle proteins, a process wherein a radical cluster of atoms
called an acetyl group attach to a protein and change its function. HATs
facilitate acetylation, and HDACs remove the acetyl group. The team
discovered that acetylation renders the muscle fiber more sensitive to
calcium, which causes the muscle to contract.

�This is a completely new process in the area of heart muscle
contraction,� Shroff said. �Acetylation is widely known to regulate such
events inside the cell nucleus as gene regulation, but it�s never before
been associated with heart muscle contraction.�
Furthermore, Shroff and his colleagues could intervene in this
microscopic process to control heart muscle contraction. By inhibiting
HDACs, they increased the calcium sensitivity of the muscle fibers and
strengthened contraction.

As a possible treatment for such conditions as congestive heart failure,
this technique could present an alternative to current therapies that
counteract heart muscle weakness by boosting cellular calcium content,
Shroff said. The heightened calcium improves muscle contraction but also
results in more energy consumption in hearts that often are
energy-starved to begin with.

In contrast, inhibiting HDAC alters a natural process to make heart
muscle more sensitive to the prevailing level of calcium, he said.

�We did not create this process�we are just manipulating what is already
there,� Shroff explained. �The physiology to block HDAC is already
there, and we just took advantage of that. This perturbation does not
require greater mobilization of calcium, so we won�t end up with
increased cardiac energy consumption. That�s been the Achilles heel of
treatment so far.�

The team�s next step involves examining HAT- and HDAC-driven regulation
of cardiac contraction in the whole animal rather than just muscle
samples. Then it can better determine the overall significance of the
newly discovered process to the intact heart function and its
therapeutic potential.

�We want to see how much protein acetylation matters when operating
alongside all the other processes in the heart and the body,� Shroff
said. �If this process is shown to be significant under these
conditions, it will be an exciting finding.�

The project was funded by a grant from the National Institutes of Health.
Adapted from materials provided by University of Pittsburgh.

J Biol Chem. 2008 Apr 11;283(15):10135-46. Epub 2008 Feb 4.� LinkOut

HDAC4 and PCAF Bind to Cardiac Sarcomeres and Play a Role in Regulating
Myofilament Contractile Activity.
* Gupta MP,
* Samant SA,
* Smith SH,
* Shroff SG.

Department of Surgery, Committee on Molecular Medicine, Biological
Science Division, University of Chicago, Chicago, Illinois 60637.

Reversible acetylation of lysine residues within a protein is considered
a biologically relevant modification that rivals phosphorylation (
Kouzarides, T. (2000) EMBO J. 19, 1176-1179 ). The enzymes responsible
for such protein modification are called histone acetyltransferases
(HATs) and deacetylases (HDACs). A role of protein phosphorylation in
regulating muscle contraction is well established ( Solaro, R. J., Moir,
A. J., and Perry, S. V. (1976) Nature 262, 615-617 ). Here we show that
reversible protein acetylation carried out by HATs and HDACs also plays
a role in regulating the myofilament contractile activity. We found that
a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac
myofilaments. Primary cultures of cardiomyocytes as well as mouse heart
sections examined by immunohistochemical and electron microscopic
analyses revealed that both HDAC4 and PCAF associate with the Z-disc and
I- and A-bands of cardiac sacromeres. Increased acetylation of
sarcomeric proteins by HDAC inhibition (using class I and II HDAC
inhibitors or anti-HDAC4 antibody) enhanced the myofilament calcium
sensitivity. We identified the Z-disc-associated protein, MLP, a sensor
of cardiac mechanical stretch, as an acetylated target of PCAF and
HDAC4. We also show that trichostatin-A, a class I and II HDAC
inhibitor, increases myofilament calcium sensitivity of wild-type, but
not of MLP knock-out mice, thus demonstrating a role of MLP in
acetylation-dependent increased contractile activity of myofilaments.
These studies provide the first evidence that HATs and HDACs play a role
in regulation of muscle contraction.

PMID: 18250163

Congest Heart Fail. 2007 Jul-Aug;13(4):193-9. Related Articles, LinkOut
�
The roles of selenium and mercury in the pathogenesis of viral
cardiomyopathy.
Cooper LT, Rader V, Ralston NV.

Department of Medicine, Division of Cardiovascular Diseases, Mayo
Clinic, Rochester, MN 55905, USA.

Research on the pathogenesis of nonischemic dilated cardiomyopathy (DCM)
has largely been focused on the role of viral pathogens and altered
immunity. Trace elements have only rarely been considered; however,
clinical observations that trace elements influence cardiovascular
disease have been made in populations with extreme dietary deficiency or
occupational exposure. Recently, animal models of DCM have been used to
explore interactions among trace elements, viral pathogens, and the
immune system. Discovery of interactions of trace elements with causes
for DCM has heightened awareness of potential contributions of
environmental variables to DCM pathogenesis. This article reviews the
present knowledge regarding trace elements, in particular selenium and
mercury, in the pathogenesis of viral and immune-mediated DCM. Based on
recent studies, the authors propose a novel paradigm for the
pathogenesis of viral DCM that incorporates trace element imbalance and
its interactions with the cellular physiology of viral-induced
cardiomyocyte dysfunction.
Publication Types:
* Review

PMID: 17673870

Biol Trace Elem Res. 2000 Winter;78(1-3):131-47
�
Trace element distribution in heart tissue sections studied by nuclear
microscopy is changed in Coxsackie virus B3 myocarditis in methyl
mercury-exposed mice.

Ilback NG, Lindh U, Wesslen L, Fohlman J, Friman G.
Toxicology Division, National Food Administration, Uppsala, Sweden.

Methyl mercury (MeHg) has been shown to change Coxsackie virus type B3
(CB3) myocarditis in a direction compatible with the development of
chronic disease. Murine models of CB3 myocarditis closely mimic the
pathogenesis in humans. There are also indications that metals, such as
mercury, and trace elements may interact and adversely affect viral
replication and development of inflammatory lesions. The effects of
low-dose MeHg exposure on myocardial trace element distribution, as
determined by means of nuclear microscopy, was studied in CB3
myocarditis. Balb/c mice were fed a MeHg-containing diet (3.9 mg/kg
diet) for 12 wk prior to infection. Areas of inflammatory lesions in the
myocardium were identified by traditional histologic examination, and
serial tissue sections in these selected areas were used for immune
histology (macrophages), in situ hybridization of virus genomes, and
nuclear microscopy of tissue trace element distribution. Areas with no
inflammation or virus were compared with areas of ongoing inflammation
and viral replication. In the inflammatory lesions of MeHg-exposed mice
as compared to nonexposed mice, the myocardial contents of calcium (Ca),
manganese (Mn), and iron (Fe) were significantly increased, whereas the
zinc (Zn) content was decreased. The increased Ca and decreased Zn
contents in the inflamed heart may partly explain a more severe disease
in MeHg-exposed individuals. Although not significant in the present
study, with a limited number of mice, the inflammatory and necrotic
lesions in the ventricular myocardium on d 7 of the infection was
increased by 50% (from 2.2% to 3.3% of the tissue section area) in
MeHg-exposed mice and, also, there was a tendency of increased
persistence of virus with MeHg exposure. No increased MeHg uptake,
either in the inflammatory lesions or in the areas of noninflamed heart
tissue in infected mice, could be detected. The present results indicate
that a "competition" exists between potentially toxic heavy metals from
the environment/diet and important trace elements in the body and that a
disturbed trace element balance adversely influences the development of
pathophysiologic changes in inflammatory heart disease.
Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 11314973

J Am Coll Cardiol. 1999 May;33(6):1578-83. Related Articles, Cited in
PMC, LinkOut
�
Comment in:
* J Am Coll Cardiol. 2000 Mar 1;35(3):819-20.

Marked elevation of myocardial trace elements in idiopathic dilated
cardiomyopathy compared with secondary cardiac dysfunction.
Frustaci A, Magnavita N, Chimenti C, Caldarulo M, Sabbioni E, Pietra R,
Cellini C, Possati GF, Maseri A.
Department of Cardiology, Catholic University, Rome, Italy.
OBJECTIVES: We sought to investigate the possible pathogenetic role of
myocardial trace elements (TE) in patients with various forms of cardiac
failure. BACKGROUND: Both myocardial TE accumulation and deficiency have
been associated with the development of heart failure indistinguishable
from an idiopathic dilated cardiomyopathy. METHODS: Myocardial and
muscular content of 32 TE has been assessed in biopsy samples of 13
patients (pts) with clinical, hemodynamic and histologic diagnosis of
idiopathic dilated cardiomyopathy (IDCM), all without past or current
exposure to TE. One muscular and one left ventricular (LV)
endomyocardial specimen from each patient, drawn with metal
contamination-free technique, were analyzed by neutron activation
analysis and compared with 1) similar surgical samples from patients
with valvular (12 pts) and ischemic (13 pts) heart disease comparable
for age and degree of LV dysfunction; 2) papillary and skeletal muscle
surgical biopsies from 10 pts with mitral stenosis and normal LV
function, and 3) LV endomyocardial biopsies from four normal subjects.
RESULTS: A large increase (>10,000 times for mercury and antimony) of TE
concentration has been observed in myocardial but not in muscular
samples in all pts with IDCM. Patients with secondary cardiac
dysfunction had mild increase (< or = 5 times) of myocardial TE and
normal muscular TE. In particular, in pts with IDCM mean mercury
concentration was 22,000 times (178,400 ng/g vs. 8 ng/g), antimony
12,000 times (19,260 ng/g vs. 1.5 ng/g), gold 11 times (26 ng/g vs. 2.3
ng/g), chromium 13 times (2,300 ng/g vs. 177 ng/g) and cobalt 4 times
(86,5 ng/g vs. 20 ng/g) higher than in control subjects. CONCLUSIONS: A
large, significant increase of myocardial TE is present in IDCM but not
in secondary cardiac dysfunction. The increased concentration of TE in
pts with IDCM may adversely affect mitochondrial activity and myocardial
metabolism and worsen cellular function.

PMID: 10334427
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