The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 17 No. 9 • October 2014


IMPORTANT NEW DISCOVERY!
NEW WAY TO PREVENT ATHEROSCLEROSIS

Answer to Question of Why Atherosclerotic Plaques
Tend to Form in Areas of Disturbed

Blood Flow Points to Way to Prevent Formation of
Plaques in Those Areas

What could be an immense advance in the prevention of atherosclerosis was the discovery, reported in July 2014 The Journal of Clinical Investigation,1 of the underlying cause of plaque formation in areas of disturbed blood flow, such as where arteries bifurcate. It has long been known that laminar (shear) flow in arteries is atheroprotective whereas turbulent blood flow in arteries induces the initiation and development of atherosclerotic plaques, leading to increased rate of formation of plaques in areas with disturbed blood flow. But why?

The new paper1 reports that changes in gene expression take place in endothelial cells in response to exposure to laminar (shear) flow as compared to disturbed (turbulent) blood flow. These gene expression changes were found to be under the control of epigenetic mechanisms — hypermethylation within the promoter regions of 11 genes sensitive to mechanical stimulation in endothelial cells occurred when exposed to turbulent blood flow. The hypermethylation, acting as a sort of mechanosensitive master switch, altered the expression of these arterial genes (without changing the DNA sequence) to promote atherosclerosis rather than to protect against it.

The researchers were able to restore methylation status to normal (correcting the hypermethylation) by treating cells from C57BL/6 mice exposed to partial carotid ligation surgery (to induce turbulent flow) with the demethylating drug 5-aza-2’-deoxycytidine, FDA approved and currently used for the treatment of certain types of cancer, such as leukemia.

Not discussed in this paper but very relevant to its findings, however, there are natural products that also act as demethylating agents, including curcumin (found in turmeric root) and EGCG (epigallocatechin-gallate, found in particularly high concentrations in green tea).2,3 We have written about the potential medical applications of these naturally occurring demethylating agents in earlier newsletters. See, for example, in our Nov. 2013 newsletter [“Epigenetic Changes in Expression of Genes via DNA Methylation” in Life Extension News, Volume 16, Number 10], our article on how demethylating agents can restore the sensitivity of diffuse B-cell lymphoma to chemotherapy.4 We are on the lookout for data on how potently the natural demethylating agents work in comparison to the drug 5-aza-2’-deoxycytidine.

The researchers found that subjecting the mouse carotid arteries to partial carotid ligation resulted (as detected by mRNA array) an increase in the expression of DNA methyltransferase (DNMT) by about 2.4 fold higher in the left carotid artery as compared to the right carotid artery that was exposed to shear (not disturbed) flow. They also reported that the increased DNMT expression took place in both endothelial and smooth muscle cells. These effects were confirmed using cultured human endothelial cells (HUVECs) exposed to oscillatory shear stress to mimic disturbed flow. DNMT1, but not DNMT3a or DNMT3b, were regulated in this flow-dependent manner in the above studies.

Surprisingly, the emergence of DNA methylation as a field of scientific research took place 35 years ago.5 For those interested in the technical details, here’s how it (methylation) takes place: DNA methyltransferases add (write) a methyl group to the 5 position of the cytosine pyrimidine ring.5 Cytosine is one of the four bases of DNA. Epigenetic modulation of gene expression (via methylation or acetylation of DNA) is being discovered to importantly regulate how the exact same DNA code gets translated. For example, neuronal activity has been reported to modify DNA methylation in the adult brain.6

Extracellular superoxide dismutase in human monocytes/macrophages is an important protective mechanism against atherosclerosis by inhibiting the oxidation of LDL via the acceleration of superoxide dismutation.6B Here, researchers used the DNA methyltransferase inhibitor 5-azacytidine to demethylate genes whose expression was suppressed by hypermethylation, providing another example of how epigenetic mechanisms have been revealed to play a major role in atherosclerosis.

References

1. Dunn, Qiu, Kim, et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. FASEB J. 124(7):3187–3199 (2014).
2. Fang, Wang, Ai, et al. Tea polyphenol (-)-epigallocatehin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563–70 (2003).
3. Liu Z, Liu S, Xie Z, et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706–709 (2009); Du, Xie, Wu, et al. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Canc. 64(8):1228–35 (2012).
4. Clozel et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov. 3(9):1–18 (2013).
5. Ladd. Epigenetic factors in neurodegeneration. Curr Tran Geriatr Gerontol Rep. 1:206–13 (2012).
6. Guo, Ma, Mo, et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nature Neurosci. 14(10):1345–51 (2011).
6B. Kamiya, Machiura, Makino, et al. Epigenetic regulation of extracellular superoxide dismutase in human monocytes. Free Rad Biol Med. 61:197–205 (2013).

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