A rusty old heart: Hypertension and oxidative DNA damage in the cardiovascular system

We recently learned that the gene MTH1 plays a role in defending the brain against oxidative DNA damage. The Mth1 protein dephosphorylates an oxidized nucleotide (8-oxo-dGTP), preventing 8-oxo-dG incorporation into new DNA. MTH1-/- knockout mice suffer from increased levels of DNA damage and oxidatively induced cell death.

It appears that MTH1 also protects the heart from oxidative damage. Ohtsubo et al. demonstrate that the frequency of MTH1 expression increases in the aortic and cardiac smooth muscle cells of hypertensive rats, whose cardiovascular tissue exhibits high levels of DNA damage:

… Little attention has been given to the biological significance of 8-oxo-dG accumulation in cardiovascular tissues during the different stage of hypertension and its prevention. We thus investigated the levels and localization of both 8-oxo-dG accumulation and expression of MTH1, which hydrolyzes 8-oxo-dGTP to prevent its incorporation into DNA, in the thoracic aorta prepared from stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wister–Kyoto rats (WKY), aged 5–32 weeks. …[T]he levels of nuclear 8-oxo-dG in the aorta increased significantly in SHRSP, but not WKY, with aging. Immunohistochemical study revealed that both TUNEL reactivity and 8-oxo-dG immunoreactivity were increased in smooth muscle cells (SMC) and endothelial cells (EC) of the aorta with aging…. The number of 8-oxo-dG and TUNEL positive cells in EC, but not in SMC, was significantly higher in SHRSP than WKY at 32 weeks of age. In contrast, the expression levels of Mth1mRNA and MTH1 protein in the aorta were similarly decreased both in SHRSP and WKY with aging. However, the number of MTH1 expressing EC was remarkably increased in the older SHRSP compared to the younger ones or age-matched WKY. Hypertension significantly increased not only 8-oxo-dG accumulation but also the expression of MTH1 in EC of the aorta during aging. While accumulation of 8-oxo-dG in SMC of the aorta was slightly increased, the expression of MTH1 protein in SMC was rather decreased by hypertension. We thus suggest that MTH1 may protect EC in the aorta from the oxidative damage increased by hypertension.

To summarize and restate: 8-oxo-dG incorporation into DNA is higher in hypertensive rats, i.e., the steady state levels of DNA damage are higher than in the healthy wildtype. Both hypertensive and wildtype rats generally decrease MTH1 expression over the course of aging — but in the hypertensive animals, the number of cells expressing the gene increase

The interpretation favored by the authors is that MTH1 is behaving like a housekeeping gene in early life but a stress response gene in late life: In young animals, basal levels of MTH1expression protect the heart against oxidative DNA damage. (Hypertensive animals presumably have a higher rate of oxidation; hence the same level of protection still results in a higher level of 8-oxo-dG incorporation.) Over the course of normal aging, MTH1 expression goes down, resulting in less protection and higher levels of damage. In older animals, the cells expressing MTH1 are presumably ones that have received the highest levels of oxidative damage, and are consequently inducing an anti-oxidant regulon that includes MTH1.

That, as I say, is the author’s interpretation. I’m perplexed by one issue: If increased oxidative damage causes induction of an anti-oxidant regulon, it seems like wildtype and hypertensive animals should show a steady increase in MTH1 expression over the course of aging.

Determining whether MTH1 is truly protective will await studies in knockout mutants, the key question being whether MTH1-/- animals develop hypertension (in the same way that they precociously develop Parkinson’s-like damage, as well as being more sensitive to stressors that cause this type of insult.) A knockout mouse already exists, but I don’t know whether the mouse models of hypertension are as well-developed as they are in the rat.

Nonetheless, a gene with a very specific biochemical function (preventing incorporation of a specific oxidized nucleotide into DNA) that might protect two wildly different (and wildly important) tissues from age- and disease-related damage is well worth further study. MTH1 is a gene to watch.