Department of Medicine, Cell Biology, and Genetics Duke University Medical Center Durham, North Carolina, USA h.rockman@duke.edu
Heart failure and pathological overgrowth of the heart often occur hand in hand. New data on a biomechanical sensor challenge the viewpoint that cardiac hypertrophy causes heart failure (pages 68−75).
The main function of the heart is to provide adequate delivery of oxygen to meet the metabolic demands of the body under conditions of normal and increased workload. Although the performance of the heart is well maintained over a wide range of physiological stressors, increased biomechanical stress from either exercise or disease can drive morphological changes in the heart muscle, known as cardiac hypertrophy. Cardiac hypertrophy is an increase in mass of the heart due primarily to an increase in cell size, which under certain conditions progresses into heart failure. The molecular and cellular mechanisms that are at the base of the pathological transition from cardiac hypertrophy to cardiac failure have been the subject of intense investigation for over a half century. In this issue, Brancaccio et al.1 address the fundamental question of how biomechanical stress translates into biochemical changes inside a heart muscle cell. They show that the integrin-bound protein melusin acts as a biomechanical sensor, and that it is protective against the adverse effects of pressure overload.
Pressure-overload−induced cardiac hypertrophy, such as that caused by chronic hypertension, is triggered by two major types of input that result in an enlarged muscle: (1) mechanical stress and (2) neural and humoral factors that activate growth factor receptor tyrosine kinases (RTKs), cytokine receptors and G-protein-coupled receptors2 (GPCRs), particularly those that couple to the Gq class of heterotrimeric guanine-nucleotide binding regulatory proteins (G proteins)3. Signals originating from all of these pathways converge intracellularly and result in altered gene expression and protein synthesis that lead to an enlarged heart.
Although many of the factors that initiate GPCR-mediated hypertrophy have been studied extensively, the role of biomechanical sensor molecules in cardiac hypertrophy is less understood. Transduction of mechanical stress into biochemical signals is largely mediated by a group of cell surface receptors called integrins, which link the extracellular matrix (ECM) to the cellular cytoskeleton, thus providing physical integration between the outside and the inside of the cell. Activation of integrins by different ligands in the ECM (for example, collagen, fibronectin and laminin) initiates signaling in multiple intracellular pathways through integrin-bound proteins that regulate gene expression, cell growth and survival4,
5. One of the candidate proteins to act as a biomechanical sensor in this pathway is melusin, which interacts with the cytosolic domain of integrin and is expressed exclusively in skeletal and cardiac muscle5.
In this new report1, the authors examined the role of melusin in the development of cardiac hypertrophy in response to two different models. Mice that are genetically deficient for the melusin gene were exposed to either biomechanical stress through physical constriction of the aorta7, or hormonally induced cardiac hypertrophy through activation of Gq-coupled receptors at doses that do not induce elevation in blood pressure. The most important finding of this study is that melusin was critical only for the development of biomechanically induced cardiac hypertrophy, whereas it was not involved in hormonally induced hypertrophy or in normal heart function and development. Moreover, mice that were melusin-deficient developed heart failure in response to biomechanical pressure overload. The authors further identified a role for melusin in the activation of a specific signaling pathway involved in mediating the hypertrophic response. Together their data indicate that the actions of melusin are restricted to integrin-mediated signaling pathways activated by mechanically induced pressure overload.
A long-standing controversy has centered on whether the development of cardiac hypertrophy is protective against the deterioration into heart failure. The long-held view has been that cardiac hypertrophy in response to pathological overload serves to restore heart muscle stress back to normal and counteracts the progressive deterioration of cardiac function. However, recent studies have demonstrated that cardiac hypertrophy is not critical for the prevention of cardiac deterioration. Rather it is the chronic activation of Gq-coupled receptors and other signaling pathways that is harmful8,
9. Given the observation that the lack of melusin prevents the development of cardiac hypertrophy and promotes heart failure, Brancaccio et al. deduce that hypertrophy prevents the deterioration in cardiac function. While their data are certainly intriguing, we offer a different interpretation of it. In our opinion, progression to cardiac failure does not depend on the phenotype of hypertrophy, but rather is related to the intricate balance between the activation of protective and deleterious signaling pathways. In this regard, the novel contribution of Brancaccio et al. lies in the identification of a molecule that is involved in a hypertrophic signaling pathway and is also protective against the development of heart failure. In contrast, the activation of Gq-coupled receptor signaling pathways, which also culminates in the same phenotype of cardiac hypertrophy, is deleterious and often progresses to cardiac enlargement and heart failure9,
10. It is not the hypertrophy per se that determines a detrimental outcome, but rather the different signaling pathways that are activated in response to the chronic overload state of the heart. Indeed, a recent study supports the finding of a protective role for integrins against the development of pressure-overload−induced heart failure4.
The identification of the precise intersection between the integrin−melusin pathway and other signaling pathways will be of great importance in understanding the complexity of the hypertrophic response that leads to heart failure. Further investigation will likely provide the exact molecular mechanisms involved in pressure-overload−induced cardiac hypertrophy and perhaps lead to novel therapeutic opportunities for the treatment of this deadly disease.
Brancaccio, M. et al. Melusin, a muscle-specific integrin 1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nature Med.9, 68–75 (2003). | Article | PubMed | ISI | ChemPort |
Brancaccio, M. et al. Melusin is a new muscle-specific interactor for (1) integrin cytoplasmic domain. J. Biol. Chem.274, 29282–29288 (1999). | Article | PubMed | ISI | ChemPort |
Rockman, H.A. et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc. Natl. Acad. Sci. USA88, 8277–8281 (1991). | PubMed | ChemPort |
1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nature Med. 9, 68–75 (2003). | 
q signaling: A common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc. Natl. Acad. Sci. USA 95, 10140–10145 (1998). | 
