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Translating Cellular Mechanisms to Therapeutic Targets

Annual WG Meeting Report

Lake Como and its mountainous shoreline provided the beautiful natural backdrop for the first joint meeting of the Working Groups on Myocardial Function and Cellular Biology of the Heart. Organised by Jean-Luc Balligand, Denise Hilfiker-Kleiner and Rainer Schulz, the meeting was held within the fine gardens and historic building of the Villa Monastero, until 1567 a Cistercian convent, and then a noble family home, before becoming a conference centre. Eighty people filled the Enrico Fermi salon (formerly the convent chapel), adjacent rooms and the cloister for seven plenary sessions and three poster sessions. Leading experts and younger workers all contributed in a very free exchange of knowledge and ideas, and sessions were characterised by informality and long discussions.

Basic Science

The meeting opened with a session focused on roles and mechanisms of action of nitric oxide (NO).

Dr Elizabeth Murphy (Bethesda, USA) gave an outstanding overview of protein nitrosylation in the heart. 
S-nitrosylation is a redox-sensitive post-translational modification that has the potential to provide fine local control of protein function. As a mechanism of NO action, S-nitrosylation is independent of guanylyl cyclase activity and may represent an important mechanism by which NO is associated with cytoprotection in oxidative stress conditions such as ischemia-reperfusion since S-nitrosylation protects proteins from oxidative damage. An interesting dimension is the estrogen-associated cardioprotection in females. Mediated by estrogen receptorb, this is an NO-dependent, but guanylyl cyclase-independent phenomenon and likely to involve S-nitrosylation.

NO regulation of cardiac remodelling and contractility.

Dr An Moens (Utrecht, NL) and Dr Gabriele Tocchetti (Naples, IT)presented their work on aspects of NO regulation of cardiac remodelling and contractility.
Dr Moens, described studies showing that tetrahydrobiopterin (BH4) preserves eNOS coupling/dimerisation, leading to a shift towards more NO and less reactive oxygen species (ROS) production which attenuated myocardial hypertrophy and dilatation in a pressure-overload model. Dr Tocchetti's work centred around the nitroxyl (HNO) species as a potential regulator of myocyte Ca2+ handling and contractility. Ongoing studies suggest that cysteine modification in phospholamban may be a central mechanism for the increased contractility and lusitropy associated with HNO.

Mitochondria as the major source of ROS.

The second session was devoted to mitochondrial mechanisms in cardiac damage with a particular emphasis on ischemia-reperfusion. Dr Fabio Di Lisa (Padova, IT) gave an elegant account of mitochondria as the major source of ROS. He described three principal molecular sources of ROS in mitochondria: the respiratory chain;  monoamine oxidase-subtype A; and p66SHC. The latter protein translocates to mitochondria after phosphorylation and catalyses the formation of H2O2. p66-/- mutant mice are relatively protected from ischemia-reperfusion injury and they also exhibit a life-span increase of about 30%.

Role of GSK-3ß in the regulation of the mitochondrial permeability transition pore (MPTP).

Dr Di Lisa was followed by Dr Charles Steenbergen (Baltimore, USA) who addressed the controversial role of GSK-3ß in the regulation of the mitochondrial permeability transition pore (MPTP). Inhibition of GSK-3ß has been widely accepted as preventing the lethal opening of MPTP under conditions of oxidative stress but the mechanism by which this inhibitory regulation occurs is unknown. Dr Steenbergen proposed three possible models by which active GSK-3ß might modify the phopshorylation status of the VDAC component of the MPTP and thereby promote MPTP opening.

What transgenic mice or isolated (neonatal) cardiomyocytes tell us about the kinase pathways involved in cardiac hypertrophy

Dr Peter Sugden (London, UK) opened Session III by addressing the issue of what transgenic mice or isolated (neonatal) cardiomyocytes tell us about the kinase pathways involved in cardiac hypertrophy. Using examples from his own laboratory, including the effects of insulin as the classical inhibitor of GSK-3ß, Dr Sugden argued about the advantages and limitations of the respective model systems.

Dr Sylvia Gunkel (Gottingen, DE), Dr Monika Gladka (Utrecht, NL) and Dr Colin Murdoch (London, UK) then presented accounts of their experimental work assessing aspects of MLP-interacting proteins, Hand2, and Nox2 expression in regulating cardiac dysfunction, hypertrophy and remodelling.

Roles of adult cardiac progenitor cells and inflammation mechanisms

Dr Martin Bergmann and Dr Stefan Frantz (Wurtzburg, DE) led a session on the roles of adult cardiac progenitor cells and inflammation mechanisms as targets for cardiac remodelling and failure. Dr Bergmann presented seminal work on the regulation of adult cardiac stem cells differentiation by signalling elements of the Wnt/beta-catenin pathway. Using genetic mouse models with either beta-catenin deletion or stabilization, he showed that extinction of this signalling pathway is necessary for the differentiation of Sca-1 positive cardiac progenitor cells into cardiomyocytes, translating into improved infarct healing.  Dr. Frantz discussed the role of Toll-like receptors (TLR) in the early healing phase of acute myocardial infarction which is associated with a robust inflammatory response. He discussed evidence that the innate immune system, through pattern recognition receptors mediates the immune response responsible for wound healing and tissue repair. Evidence from mutant mice with knockout of TLR2  or TLR4 suggests that these components of the innate immune system play key roles in regulating extracellular matrix accumulation and ventricular dilatation after experimental infarction. 

Roles of the pro-angiogenic factor CCN-1 in myocardial infarction.

Dr Hatice Yamac (Hannover, DE) presented studies in transgenic mice assessing the roles of the pro-angiogenic factor CCN-1 in myocardial infarction.  Dr Antonio Lourenco (Porto, PO) reported the effects of a high-calorie diet in ameliorating cardiac cachexia in the monocrotaline model of pulmonary hypertension leading to cardiac failure.

A "how-to" session heard a comprehensive account from Dr Charles Steenbergen (Baltimore, USA) on approaches to, and the complexities of, measurement of cardiac metabolism. Basic methods centre around measurements of myocardial O2 consumption, the use of labelled substrates to measure rates of metabolic pathways, or techniques that provide information on substrate selection. Dr Knoell illustrated the use of the zebrafish model to discover novel genes associated with cardiovascular diseases, such as the “lost contact” zebrafish. Dr Rainer Schulz (Essen, DE) delivered a lecture on the roles of mitochondral proteins in cardioprotection. He focussed specifically on connexin-43,  found in sub-sarcolemmal mitochondria and which plays a key role in the triggering phase of ischemic preconditioning but not in postconditioning.  Dr Schulz reviewed evidence from heterozygous null mice that connexin-43 mediates mitochondrial ROS production as part of a critical signal transduction event.

New approaches to dissecting the roles and regulation of miRNAs and these with antagomirs were the focus of another session.

Antagomirs are antisense reagents that silence miRNAs and display prolonged in vivo stability and activity. Dr Thomas Thum (Wurzburg, DE) described the results of studies with antagomir-21 (antagonising miRNA) in a pressure overload model where myocyte hypertrophy and fibrosis were reduced by the antagomir. Dr Leon De Windt (Utrecht, NL) described the roles of miRNA-199b which is an NFAT target gene that is upregulated in the failing heart. Ongoing studies with antagomir-199b were providing insights into the roles of miRNA-199b in heart failure and remodelling. Dr A Haghikia (Hannover, DE) presented information on another member of the miRNA-199 family, miRNA-199a, and its regulation by STAT3. Studies with STAT3 deficient mice reveal that miRNA-199a is downregulated by STAT3 and plays a role in myocyte hypertrophy. Hamid el Azzouzi (Utrecht, NL) presented evidence that miRNA-199a and miRNA-214, both upregulated in cardiac disease, promote adverse remodelling and failure via downregulation of PPAb/d, a key regulator of myocyte metabolism.

The final scientific session addressed specific mechanisms of myocyte hypertrophic signalling. Dr Nanette Bishopric (Miami, USA) described recent work in her laboratory assessing the roles of p300 acetyltransferase in the regulation of myocyte hypertrophy. p300 is an epigenetic regulator that acetylates histones and transcription factors. It is stress-inducible in the heart and is upregulated in human heart failure, probably by stabilisation of the protein. Mice overexpressing p300 sustain smaller infarcts and less compensatory hypertrophy. Dr. Tarone illustrated protein-protein interactions between melusin, a muscle-specific stretch-sensitive protein that he previously showed to be protective against maladaptive remodelling, the chaperone hsp90 and IQGAP, thereby assembling a dynamic signalosome to coordinate adaptative hypertrophic signalling.

Dr Fischer illustrated a particular phenotype associated with cardiomyocyte-specific deletion of the transcription factor, STAT3, i.e. a loss of contractile reserve to beta-adrenergic stimulation, that may participate to the progressive development of cardiac failure in this model. Dr Santulli demonstrated the opposite effects of GRK2 and GRK5 on NF-kappaB-mediated pro-hypertrophic effects of angiotensin II in vitro and in vivo, suggesting the interest to target GRK’s to treat hypertrophic cardiomyopathy. This last session ended with a state-of-the-art lecture by Jeff Molkentin (Cincinnati, USA) who illustrated the key role of PKCalpha as a negative regulator of contractility, leading to heart failure in the hemodynamically-stressed heart, thereby highlighting the potential therapeutic use of broad-acting PKC inhibitors such as ruboxistaurin.

The meeting also included two moderated poster sessions held in a relaxed atmosphere in the beautiful rooms surrounding the “Sala Fermi”.  After the prize announcements for “best poster”, the final word went to the organizers, who thanked the faculty and attendees from both Working Groups. All showed their appreciation, for the support of the ESC Basic Cardiovascular Science Council, especially the young scientists who benefited from a travel grant thanks to the generosity of the Council. 


Special thanks went to the team of Georgia Deboone in Brussels and Céline Serio in Sophia Antipolis who, together with the help of Linda van Laake and Anne Boeter on the spot, did a great job to give us a smooth ride.
Our speakers agreed to answer your questions concerning their talks, so do not hesitate to contact them by e-mail provided on this page.