The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 17 No. 6 • July 2014


Butyrate Inhibition of Vascular Smooth Muscle
Proliferation, a Major Mechanism in Atherosclerosis,
May Be the Result of Increased Glutathione

Finally, we report a somewhat earlier (2007) paper on butyrate that found that the treatment of rat vascular smooth muscle cells (VSMC) with butyrate potently inhibited VSMC proliferation, which is important in the development of atherosclerosis.1 In the atherosclerotic process, VSMC proliferation is followed by cellular migration, where cells can migrate from the arterial media to the intima, where they continue to proliferate and, switching to an inflammatory phenotype, accumulate excessive amounts of extracellular matrix proteins and attract cholesterol laden macrophages into a developing atherosclerotic plaque.1

Earlier studies by the paper’s authors had shown that butyrate acts as an anti-proliferative agent on VSMCs. In this study,1 the researchers decided to examine further butyrate’s effects on the glutathione S-transferase (GST) family that has been reported to be upregulated in conjunction with the induction of cellular glutathione by butyrate in normal and transformed colorectal cells. The researchers had observed these changes to be induced by butyrate in VSMCs. The study1 reports that “butyrate upregulates GSTs and appropriately modulates cellular GSH [glutathione] and reactive oxygen species (ROS) levels to influence VSMC proliferation, a critical element in the pathogenesis of AT [atherosclerosis].”

The authors measured the concentration-dependent induction of GST-P1 (a member of the GST family) by butyrate. Though the VSMCs had very little expression of GST-P1 under basal conditions, 1 μM butyrate stimulated an approximately threefold increase in its expression within 48 hours. The increase continued almost linearly up to 5 μM of butyrate, but discontinued increasing after that. They found that proliferation was completely inhibited at a concentration between 5 μM and 8 μM, but observed no toxic effects at those concentrations.

We have been studying the processes by which vascular smooth muscle cells enter the pathways that lead to atherosclerosis and to later complications (such as arterial restenosis, pulmonary hypertension, and heart failure) for many years, looking for safe, effective, and inexpensive ways to intervene. We believe butyrate is an excellent candidate for prevention and possibly treatment by intervening in some of these pathways. All we need to do is consume a healthy quantity of indigestible fermentable dietary fiber, such as the long chain inulin oligofructose that we take as a supplement, and let our gut microbiota take care of the rest! They not only make short chain fatty acids, including butyrate, from this type of fiber, but some gut microbes process the fiber, creating and releasing hydrogen. Hydrogen is another atheroprotective substance, being a selective anti­oxidant that scavenges the potent oxidant peroxynitrite and hydroxyl radicals (perhaps the most damaging type of radical).2

Finally, note that glutathione peroxidase is a selenium-dependent antioxidant enzyme.


  1. Ranganna, Mathew, Yatsu, et al. Involvement of glutathione/glutathione S-transferase antioxidant system in butyrate-inhibited vascular smooth muscle cell proliferation. FEBS J. 274:5962-78 (2007).
  2. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13(6):688-94 (2007).

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