Role of somatic mutations in vascular disease formation

Abstract

Coronary artery disease, cerebrovascular disease, pulmonary artery hypertension and Alzheimer's disease all lead to substantial morbidity and mortality, and we currently lack effective treatments for these vascular diseases. Since the discovery, decades ago, that atherosclerotic lesions display clonal growth, atherosclerosis and other vascular diseases have been postulated to be neoplastic processes, arising through a series of critical somatic mutations. There is conflicting evidence supporting this but studies of DNA damage and mutagenesis, both genomic and mitochondrial, in atherosclerotic and vascular lesions, have yielded evidence that somatic mutations are involved in atherogenesis and vascular disease development. The roles of mitochondrial DNA damage, oxidative stress and signaling by members of the TGF-beta receptor family are implicated. With the increasing convenience and cost-effectiveness of genome sequencing, it is feasible to continue to seek specific genetic targets in the pathogenesis of these devastating diseases, with the hope of developing personalized genomic medicine in the future.

Figure 1

Potential mechanisms of somatic mutation in vascular disease. Reactive Oxygen Species (ROS) occur in human cells due to toxic environmental exposures, such as radiation and exposure to compounds such as polycyclic aromatic hydrocarbons (PAH) and the carcinogenic benzo[a]pyrene (B[a]P) found in tobacco smoke. These species are also formed by normal metabolism and in states of increased production of oxidants, such as during chronic inflammation or in patients with genetic predisposition. These ROS can produce damage to DNA, and the resulting byproducts can be mutagenic. Production of 5-chlorouracil, in particular, when incorporated into DNA as a deoxynucleotide, leads to mispairing with Guanine and GC to AT or AT to GC mutation. Meanwhile, the oxidative byproduct of base damage, such as 8-oxoG, may itself mispair with adenine, leading to G-to-T mutation during replication. Meanwhile, ROS may interact with polyunsaturated fatty acids, and lipid peroxidation (LPO) may occur, this leads to buildup of endproducts such as 4-hydroxy-2-nonenal (HNE), which can lead to ethno-DNA base modifications which are highly mutagenic/miscoding. If the change is not repaired, a somatic mutation occurs. These somatic mutations, which may occur in mitochondrial or chromosomal DNA, may lead have deleterious effects on the organism. If they occur in a gene which is critical for cell survival, the cell may undergo apoptosis; however, should the cell be able to survive with the mutation, important changes in cell phenotype occur, depending on the cell type. Uncontrolled proliferation may lead to atherogenesis or vascular lesion formation.