Cardiovascular Medicine: A Genomic Perspective

Cardiovascular disease remains a significant cause of morbidity and mortality in the developed world in the twenty-first century. The past fifty years of research has led to the understanding that cardiovascular disease involves complex interactions between genetic factors and “lifestyle”-based risk factors such ad smoking, high-fat diet and lack of exercise. As yet, however, identifying and understanding the molecular mechanisms underlying this complex, polygenic disease are still in its infancy. Linkage analysis and positional cloning have been used to detect monogenic diseases such as familial hyertrophic cardiomyopathy, Marfan syndrome, and Duchenne muscular dystrophy. However, even the so-called single-gene disorders are proving genetically heterogenous. Familial hypertrophic cardiomyopathy, for example, is associated with at least nine distinct sarcomere genes: ß-myosin heavy chain, α-tropomyosin, cardiac troponin 1, cardiac troponin T, cardiac myosin binding protein C, cardiac myosin regulatory light chain, cardiac myosin essential light chain, α-cardiac actin and titin [1-3]. Solving the puzzles of polygenic diseases such as atherosclerosis, hypertension and heart failure is proving even more challenging. Such diseases involve numerous genetic factors and environmental triggers during cardiac development and continuing through later age. To date, a complete understanding of these factors at the molecular level with current linkage analysis or positional cloning technology has proven elusive. The genomic-based EST approach – which has the capacity to categorize and subcategorize the genes involved in order to detect genetic changes in cardiac development and in adult disease-is proving a far more powerful technology to tackle complex disease [4, 5]. Our laboratory has been employing genomic technology and the EST approach in the exploration to identify genetic factors involved in cardiac hypertrophy and heart failure. Specifically some aspects of cardiovascular biology we aim to address: 1. How many genes are expressed in the cardiovascular system and how is their expression distributed amongst the various cell types and anatomical regions in the heart? 2. Which genes and molecular pathways are involved in the pathogenesis and progression of cardiac hypertrophy and heart failure? 3. What is the relationship between environmental factors and gene expression in the heart? 4. What significance does the alteration in the distribution of the components of the extracellular matrix play in cardiac hypertrophy and heart failure? 5. Are these common mechanisms for cardiac hypertrophy or for heart failure caused by different stimuli? Using the EST approach. we have generated ＞57,000 ESTs from several human heart and artery cDNA libraries. We estimate that we have tagged approximately 25,000 unique genes to date. Our comparison of the transcript, or EST, profiles from adult and hypertrophic (ventricle) heart suggests that protein transcripts encoding stress-related and cell-signaling proteins are upregulated in the hypertrophic heart relative to the normal adult heart. Further analysis of the expression profiles led to the indentification of ＞60 genes that may be important in the process of ventricular hypertrophy and heart failure. Some of these have been previously reported to be upregulated in cardiac hypertrophy (e.g., ANF, BNP and MLC2v) whereas many others were previously unknown (e.g., alpha-B- crystalline, PAI, CLP, CD59 antigen ) and includes many uncharacterized genes (e.g., new homologs of tropomodulin, centrosomin, and microtubule-associated protein LC3) [6,7]. Furthermore, comparing EST data for a select number of genes important to cardiovascular function has led to the identification of several preliminary single nucleotide polymorphisms (SNPs) that may be involved in the pathogenesis of cardiovascular disease [ for review see reference 8] . The generation of custom cardiovascular-based cDNA microarrays is also a powerful tool for gene profiling experiments. Profiling gene expression of heart failure using a cDNA microarray coupled with bioinformatics has allowed us to identify subsets of genes up- and down-regulated in human heart failure. OF＞7,000 genes on the microarray, 299 genes were upregulate and 26 down regulated ＞1.5-fold in heart failure. Of these, genes encoding cell signaling and cell defense proteins comprise over 30% of the upregulated genes detected in the failing heart. EST technology is a powerful tool which, when coupled with microarray technology, can narrow down the potential gene candidates and gene pathways involved in complex polygenic disease states. The application of the EST approach as well as microarray analysis to cardiovascular biology will continue to prove fruitful for the discovery of critical developmental and disease genes and provide a much-needed resource in the post-genome era of functional genomics.

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