Sci. Aging Knowl. Environ., 3 December 2003
Vol. 2003, Issue 48, p. pe33
[DOI: 10.1126/sageke.2003.48.pe33]


Coronary Artery Disease and the MEF2A Transcription Factor

Eric N. Olson

The author is in the Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA. E-mail: eric.olson{at}

Key Words: MEF2 • coronary artery disease • dominant negative • autosomal dominant

The minute-to-minute function of the cardiovascular system requires seamless connections between endothelial cells, which line the lumens of arteries and veins, and intimate interactions between endothelial and smooth muscle cells and the extracellular matrix. Lesions within the arterial wall caused by lipid accumulation or other insults can result in occlusion of the vessel and coronary artery disease (CAD), a primary cause of myocardial infarction (MI) and stroke (1). CAD is coupled to a pathogenic process in which lipids and lipoproteins accumulate in the subendothelial intimal layer of the vessel wall (Fig. 1). Monocytes (macrophage precursor cells that act as scavengers to destroy invading microorganisms) are recruited from the circulation, penetrate the lesion, and differentiate into foam cells, which eventually die and contribute to a necrotic lipid-filled plaque. Macrophages and T lymphocytes also contribute to the pathogenic process by secreting growth factors and cytokines that stimulate nearby smooth muscle cells to switch from a contractile to a proliferative phenotype and produce a fibrous extracellular matrix. Eventual rupture of the plaque into the lumen of the vessel results in formation of a blood clot (thrombus) and, often, catastrophic consequences.

View larger version (15K):
[in this window]
[in a new window]
Fig. 1. Schematic diagram of normal and diseased vessel walls. In the normal vessel wall, a layer of endothelial cells lines the lumen and is separated from a smooth muscle layer by an intimal layer. During coronary artery disease, a fibrous plaque forms between the endothelial and smooth muscle layers. Invasion by inflammatory cells (moncytes, macrophages, and T lymphocytes) further contributes to plaque growth and pathogenesis of the vessel wall.

A variety of environmental and genetic risk factors are associated with CAD, including hypercholesterolemia, hypertension, obesity, diabetes, and a family history of early CAD. However, other than identifying mutations in genes whose products are involved in lipid metabolism and the handling of cholesterol and lipoproteins, relatively little progress has been made toward identifying genes that may predispose individuals to CAD and MI.

In the 28 November 2003 issue of Science, Wang et al. describe a human pedigree with an autosomal dominant predisposition to CAD and early-onset MI (2). Affected individuals had evidence of CAD with or without MI, often before the ages of 50 for men and 55 for women, without hypercholesterolemia. A genome-wide scan for the responsible gene(s) showed linkage to a region of chromosome 15q26 that contains ~93 genes [for the relevant marker (D15S120), the lod score (logarithm of the odds ratio for linkage) was 4.19]. Among these 93 genes, MEF2A caught the authors' attention. This gene encodes a transcription factor that functions in fetal development of the cardiovascular system and in calcium-dependent signaling pathways that control cell proliferation, differentiation, and death during fetal development and in the adult (3). Sequencing of the MEF2A locus revealed a 21-nucleotide deletion that eliminated seven amino acids from the C terminus of MEF2A, apparently perturbing its transcriptional activity. This mutant version of MEF2A was named adCAD/MI1 for the first autosomal dominant CAD and MI locus.

MEF2A belongs to a family of four closely related transcription factors (MEF2A, -B, -C and -D) that are conserved from yeast to humans (4). The N termini of MEF2 proteins contain MADS and MEF2 domains. The MADS domain mediates protein dimerization and binding to AT-rich DNA sequences. The adjacent MEF2 domain is required for dimerization, high-affinity DNA binding, and interaction with cofactors (Fig. 2). The C terminus functions as a transcriptional activation domain and also has a role in nuclear localization. The deleted residues in the familial mutant of MEF2A, Gln-Pro-Pro-Gln-Pro-Gln-Pro, are conserved in MEF2A proteins from other species and in other MEF2 factors. They are contained in the region of the protein required for nuclear localization (5, 6). Not surprisingly, this mutant MEF2A protein is sequestered in the cytoplasm of transfected cells and acts as a dominant negative mutant, presumably by forming heterodimers with wild-type MEF2A monomers or cofactors such as GATA factors.

View larger version (8K):
[in this window]
[in a new window]
Fig. 2. Schematic diagram of MEF2 and its functional domains. The N-terminal region of MEF2 factors contains a MADS and a MEF2 domain, which mediate DNA binding, dimerization, and cofactor interactions. (MADS stands for MCM1 agamous deficiens serum response factor.) The transcriptional activation domain and nuclear localization sequence are located near the C terminus. A variety of developmental and stress signals regulate the activity of MEF2 by governing the association of the MADS/MEF2 domains with positive and negative cofactors and by phosphorylation of the transcriptional activation domain (shown by the encircled P's). The position of the seven-amino acid deletion associated with CAD is shown.

A hallmark of the MEF2 proteins is their propensity to associate with cell-specific and signal-dependent cofactors. Thus, the ultimate set of MEF2 target genes expressed by a cell is dependent on cellular identity and environment (3, 4). The MEF2 proteins have been shown to exert both prosurvival and proapoptotic functions and to activate genes involved in cell proliferation and genes involved in muscle differentiation, the expression of which is dependent on the termination of cell proliferation. Among the best-characterized MEF2 cofactors are muscle-specific transcription factors and chromatin remodeling enzymes, including histone acetyltransferases and deacetylases. Developmental and stress signals modulate MEF2 activity both positively and negatively by controlling its association with such cofactors and its phosphorylation state (Fig. 2) (3).

The functions of MEF2 proteins in cardiovascular development and remodeling have been studied primarily in the mouse. Mice that lack the MEF2C gene die during embryogenesis from cardiac malformations, dysregulation of contractile protein gene expression, and an arrest in vascular development (7, 8). In contrast, MEF2A knockout (null) mice die during the perinatal period from cardiac abnormalities that include fragmentation of the contractile apparatus, mitochondrial defects, arrhythmias, and pathological alterations in gene expression (9).

The phenotype of individuals that harbor the MEF2A mutation identified by Wang et al. (2) is clearly distinct from that of MEF2A null mice. The fact that coronary artery abnormalities have not been seen in heterozygous or homozygous MEF2A null mice supports the notion that the mutation in this affected pedigree creates a dominant negative version of the MEF2A protein that perturbs the activities of other MEF2 proteins, which might partially substitute for the lack of MEF2A in MEF2A null mice. However, it is also possible that mice are simply less sensitive than humans to the concentration of MEF2A protein or that the pathological consequences of MEF2A deficiency in humans are dependent on other genetic or environmental factors (diet, stress, age, and the like).

Consistent with its potential involvement in vascular function, MEF2A is expressed at high concentrations in the endothelial and smooth muscle layers of the coronary arteries. MEF2A and other MEF2 factors also have been shown to be up-regulated in smooth muscle cells within the vessel wall of balloon-injured rat carotid arteries (10).

The findings of Wang et al. raise a series of interesting questions. For example, the exact mechanism whereby the seven-amino acid deletion perturbs MEF2 function, resulting in autosomal dominant familial CAD and MI, remains to be fully defined. It is possible that this mutation simply abolishes nuclear localization and creates a dominant negative protein, but it might be expected that such a mutant would be carried into the nucleus by the wild-type MEF2A encoded by the normal allele, as well as by other MEF2 factors and cofactors.

It remains possible that the mutant protein is misfolded, thus creating a "poison peptide" that aggregates in the cytoplasm, leading to indirect pathological effects on affected cells. The cellular abnormalities responsible for CAD and MI in this pedigree also remain vague. Several possibilities warrant consideration: It seems likely that defective MEF2A acts in a cell-autonomous manner, possibly to disrupt the growth or differentiation of endothelial cells, smooth muscle cells, or both at the site of vessel pathology. Even subtle perturbation of the integrity of the vessel wall could sensitize individuals to subclinical events leading to CAD or MI. However, it is also possible that the mutation affects another cell type that indirectly alters coronary artery structure or function. For example, recruitment and infiltration of inflammatory cells play important roles in CAD pathogenesis, and MEF2 factors are expressed in circulating lymphocytes and presumably in other blood cells. Perhaps the dominant-negative MEF2 protein alters the functions of these circulating blood cells at the site of vascular lesions, in some way enhancing the disease phenotype.

Ultimately, perturbation of MEF2A function is likely to lead to CAD via the dysregulation of MEF2A target genes. The identities of the critical genes responsible for this disease phenotype remain to be determined. It is interesting to note that vascular integrity is dependent on cell-cell adhesion, and MEF2 factors have been shown to regulate the expression of cell adhesion molecules, such as integrins (11). Other downstream target genes, including those involved in cell growth, differentiation, and intercellular signaling, might also represent interesting mediators of MEF2A-dependent vessel pathology. Genome-scale gene expression analyses of vessel biopsies may shed light on which of these possibilities is most likely.

Finally, it remains to be determined whether disruption of MEF2A function is unique to this particular pedigree or will prove to be more widely associated with CAD. In this regard, Wang et al. apparently looked at three other pedigrees, none of which were found to carry the MEF2A mutation. Nevertheless, the findings of this study reveal a new function for an important transcription factor best known for its roles in muscle development, and show yet again the power of rare human mutations to illuminate basic mechanisms of human disease.

December 3, 2003
  1. J. Lusis, Atherosclerosis. Nature 407, 233-241 (2000).[CrossRef][Medline]
  2. L. Wang, C. Fan, S. E. Topol, E. J. Topol, Q. Wang, A molecular basis for coronary artery disease and acute myocardial infarction: MEF2A dysfunction. Science 302, 1578-1581 (2003).[Abstract/Free Full Text]
  3. T. A. McKinsey, C. L. Zhang, E. N. Olson, MEF2: a calcium-dependent regulator of cell division, differentiation, and death. Trends Biochem. Sci. 27, 40-47 (2002).[CrossRef][Medline]
  4. B. Black, E. N. Olson, Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell Dev. Biol. 14, 167-196 (1998).[CrossRef][Medline]
  5. Y. T. Yu, Distinct domains of myocyte enhancer binding factor-2A determining nuclear localization and cell type-specific transcriptional activity. J. Biol. Chem. 271, 24675-24683 (1996).[Abstract/Free Full Text]
  6. S. Borghi, S. Molinari, G. Razzini, F. Parise, R. Battini, S. Ferrari, The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4. J. Cell Sci. 114, 4477-4483 (2001).
  7. Q. Lin, J. Schwarz, C. Buchana, E. N. Olson, Control of mouse cardiac morphogenesis and myogenesis by the myogenic transcription factor MEF2C. Science 276, 1404-1407 (1997).[Abstract/Free Full Text]
  8. Q. Lin, J. Lu, H. Yanagisawa, R. Webb, G. E. Lyons, J. A. Richardson, E. N. Olson, Requirement of the MADS box transcription factor MEF2C for vascular development. Development 125, 4565-4574 (1998).[Abstract]
  9. F. J. Naya, B. L. Black, H. Wu, R. Bassel-Duby, J. A. Richardson, J. A. Hill, E. N. Olson, Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat. Med. 8, 1303-1309 (2002).[CrossRef][Medline]
  10. B. Firulli, J. M. Miano, W. Bi, A. D. Johnson, W. Casscells, E. N. Olson, J. J. Schwarz, Myocyte enhancer binding factor-2 expression and activity in vascular smooth muscle cells. Circ. Res. 78, 196-204 (1996).[Abstract/Free Full Text]
  11. G. Ranganayakulu, B. Zhao, A. Dokidis, J. D. Molkentin, E. N. Olson, R. A. Schulz, A series of mutations in the D-MEF2 transcription factor reveals multiple functions in larval and adult myogenesis in Drosophila. Dev. Biol. 170, 664-678 (1995).[CrossRef][Medline]
Citation: E. N. Olson, Coronary Artery Disease and the MEF2A Transcription Factor. Sci. Aging Knowl. Environ. 2003 (48), pe33 (2003).

Science of Aging Knowledge Environment. ISSN 1539-6150