Genetic instability and atherosclerosis: can somatic mutations account for the development of cardiovascular diseases?

Abstract

Several observations suggest that cancer and atherosclerosis may entail fundamentally common biological mechanisms. The accumulation of lipids and the proliferation of smooth muscle cells (SMCs) are the main histological features of sclerotic plaque formation. The most prominent theory concerning the pathophysiological mechanisms of atherosclerotic plaque formation is the “inflammatory response to injury” hypothesis, which states that SMC proliferation is an inflammation‐fibroproliferative reaction to different insults to the artery wall. However, recent evidence suggests that alterations at the DNA level may contribute significantly to the development of the disease. In accordance with these findings, the “monoclonal” hypothesis of atherosclerosis has been suggested. This hypothesis proposes that atherosclerosis begins as a mutation or viral infection, transforming a single, isolated smooth muscle cell into the progenitor of a proliferative clone, as seen in carcinogenesis. Studies of DNA damage in atherosclerotic tissues are lacking. Biological evidence for the hypothesis that cancer and atherosclerosis may share pathological mechanisms is discussed, emphasizing the need to perform studies investigating the involvement of somatic mutations in heart diseases. Environ. Mol. Mutagen. 35:265–269, 2000 © 2000 Wiley‐Liss, Inc.

An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?

“…As a clone divides, replicating cells accumulate mutations that can provide a selective advantage over normal tissue, ultimately leading to a cancer 181 . Consistent with the idea that clonal expansion in humans leads to DNA damage, there are reports of mutations and DNA damage in the plaque 171, 185– 216 .…”

An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?

“…As a clone divides, replicating cells accumulate mutations that can provide a selective advantage over normal tissue, ultimately leading to a cancer 181 . Consistent with the idea that clonal expansion in humans leads to DNA damage, there are reports of mutations and DNA damage in the plaque 171, 185– 216 .…”

Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models

“…One possibility is that the differential activation of VSMCs we observe is due to the observed heterogeneity between cells in healthy vessels10. Future studies should reveal whether limitation of VSMC contribution to disease-associated cell accumulation in major arteries to a few mature VSMCs that proliferate extensively is associated with somatic mutation29, a preselected progenitor pool primed by epigenetic heterogeneity, as suggested for neomuscularization of distal pulmonary arterioles30, or caused by the rare stochastic activation of an equipotent population.…”

Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies

“…This leads to a decrease in the activity of transport RNA-Val. This mutation is associated with hypertrophic cardiomyopathy [ 256 ] and is also found in ischemic heart disease [ 257 ]. A3243G, C3256T, and A3260G are nucleotide substitutions located in the gene of RNA-Leu transfer (recognition codon UUR), which cause a defect in RNA-Leu transfer and lead to a decrease in its activity.…”

An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?

“…As a clone divides, replicating cells accumulate mutations that can provide a selective advantage over normal tissue, ultimately leading to a cancer 181 . Consistent with the idea that clonal expansion in humans leads to DNA damage, there are reports of mutations and DNA damage in the plaque 171, 185– 216 .…”

Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models

“…One possibility is that the differential activation of VSMCs we observe is due to the observed heterogeneity between cells in healthy vessels10. Future studies should reveal whether limitation of VSMC contribution to disease-associated cell accumulation in major arteries to a few mature VSMCs that proliferate extensively is associated with somatic mutation29, a preselected progenitor pool primed by epigenetic heterogeneity, as suggested for neomuscularization of distal pulmonary arterioles30, or caused by the rare stochastic activation of an equipotent population.…”

Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies

“…This leads to a decrease in the activity of transport RNA-Val. This mutation is associated with hypertrophic cardiomyopathy [ 256 ] and is also found in ischemic heart disease [ 257 ]. A3243G, C3256T, and A3260G are nucleotide substitutions located in the gene of RNA-Leu transfer (recognition codon UUR), which cause a defect in RNA-Leu transfer and lead to a decrease in its activity.…”

An update on clonality: what smooth muscle cell type makes up the atherosclerotic plaque?

“…As a clone divides, replicating cells accumulate mutations that can provide a selective advantage over normal tissue, ultimately leading to a cancer 181 . Consistent with the idea that clonal expansion in humans leads to DNA damage, there are reports of mutations and DNA damage in the plaque 171, 185– 216 .…”

Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models

“…One possibility is that the differential activation of VSMCs we observe is due to the observed heterogeneity between cells in healthy vessels10. Future studies should reveal whether limitation of VSMC contribution to disease-associated cell accumulation in major arteries to a few mature VSMCs that proliferate extensively is associated with somatic mutation29, a preselected progenitor pool primed by epigenetic heterogeneity, as suggested for neomuscularization of distal pulmonary arterioles30, or caused by the rare stochastic activation of an equipotent population.…”

Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies

“…This leads to a decrease in the activity of transport RNA-Val. This mutation is associated with hypertrophic cardiomyopathy [ 256 ] and is also found in ischemic heart disease [ 257 ]. A3243G, C3256T, and A3260G are nucleotide substitutions located in the gene of RNA-Leu transfer (recognition codon UUR), which cause a defect in RNA-Leu transfer and lead to a decrease in its activity.…”