HDACs regulate contraction by sensitizing heart muscle to calcium; might explain mercury ac***ulation in cardiomyopathy

For quite a while now, mercury ac***ulation 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 ac***ulation.

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.

³This is a completely new process in the area of heart muscle 
contraction,² Shroff said. ³Acetylation is widely known to regulate such 
events inside the cell nucleus as gene regulation, but it¹s never before 
been associated with heart muscle contraction.²
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.

³We did not create this process‹we are just manipulating what is already 
there,² Shroff explained. ³The 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 won¹t end up with 
increased cardiac energy consumption. That¹s been the Achilles heel of 
treatment so far.²

The team¹s 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.

³We want to see how much protein acetylation matters when operating 
alongside all the other processes in the heart and the body,² Shroff 
said. ³If this process is shown to be significant under these 
conditions, it will be an exciting finding.²

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 incor****ates 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 im****tant 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 Sup****t, 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 ac***ulation 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 *****sed 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