In a recent study gene switching mechanism of resveratrol and longevinex was studied. Three weeks of oral resveratrol or Longevinex® administration prior to an induced heart attack returned microRNA activity close to their pre-event levels in excised animal hearts. Among thousands of microRNA's studied, just six attributed to the gene switching events. Out of the six, four microRNA was regulated by Longevinex® and two microRNA was regulated by resveratrol.
A pre-conditioning effect with resveratrol and Longevinex® had already been demonstrated in prior studies where these small molecules activate antioxidant defenses (nitric oxide, heme oxygenase, adenosine) prior to a heart attack, thus limiting damage in the event of an abrupt halt in the delivery of oxygenated blood to the heart.
This newly published study in the PLoS ONE
(Public Library of Science) journal sought to compare and contrast the gene switching pattern for both plain resveratrol and resveratrol in a matrix with other small molecules (Longevinex®) following an induced blockage of circulation in excised animal hearts.
MicroRNA is a mechanism within living cells that switches genes. MicroRNA's are short segments of RNA that turn off gene protein-making machinery (called gene expression) when microRNA meshes with messenger RNA.
First thought to exert a minor influence over the human genome (library of genes), microRNA's are now more fully recognized as "the genome's guiding hand" - a fundamental regulator of over 90% of human genes. MicroRNA appear to exert a stronger influence over the human genome than two other known mechanisms (methylation and histone modification) of gene regulation. MicroRNAs exceed the biological action of most drugs, which are largely targeted at single genes, while microRNAs regulate complex networks of genes, there is feverish work being done to create drugs that influence microRNA.
Beyond gene switching
Of course, the objective is to produce health benefits, not just switch genes. Indeed, these small molecules did just that. Plain resveratrol and Longevinex® both protected heart tissues and reduced the size of a heart attack, as measured by the amount of scar tissue (fibrosis).
Longevinex® reduced the size of a heart attack (from ~35% without treatment to ~20% scar tissue with treatment) in a superior manner to plain resveratrol (from ~35% to ~24% scar tissue), and reduced death of heart muscle cells (cardiomyocytes) from ~17% without treatment to ~9% with Longevinex® (48% reduction in cell death), compared to a decline from ~17% to ~12% with plain resveratrol (20% reduction in cell death).
While plain resveratrol modestly improved the pumping pressure of the heart (from ~75 to ~90 millimeters of mercury pressure; 20% improvement), Longevinex® doubled heart pumping pressure (from ~70 to ~140 millimeters of mercury pressure; 100% improvement) compared to no treatment at the two-hour point following an experimentally-induced heart attack.
Also at the two-hour point, Longevinex® improved blood flow in the aorta (first blood vessel outside the pumping side of the heart) from ~15 milliliters per minute without treatment to ~26 milliliters per minute (73% improvement), while resveratrol improved blood flow from ~14 milliliters per minute without treatment to ~21 milliliters per minute (50% improvement).
Back to microRNA switching
Upon analysis, it became clear that Longevinex® exerted the greatest influence over the top 25 significantly differentiated microRNA's in rodent heart tissue. Longevinex® exceeded the effect of resveratrol in 15 of the 25 microRNA's.
Comparative analysis of three key microRNA (microRNA 20b, 21, 539) are instructive.
Longevinex® profoundly down-regulated microRNA 20b (-1366-fold) compared to plain resveratrol (-189-fold), a microRNA that exerts control over a gene (hypoxia inducing factor, or HIF-1 alpha) that adapts malignant cells to a low oxygen environment. MicroRNA 20b also exhibits control over growth factors (such as vascular endothelial growth factor, aka VEGF). The strong silencing (switching off) of HIF-1 alpha via microRNA 20b would be desirable, for example, to inhibit formation of new blood vessels that feed tumors and which invade the retina at the back of the eyes.
Prior to an induced heart attack, microRNA 21 was tremendously up-regulated (up 391.4-fold) by resveratrol and Longevinex® (up 760.9-fold), was lowered considerably after a heart attack (-4.0), then returned to up-regulation following a heart attack by resveratrol (up 61.5) and Longevinex® (up 59.3), which suggests protective pre-conditioning prior to the event.
MicroRNA 539 exhibited the highest level of up-regulation (214 fold) following a heart attack, which suggests a protective response. Resveratrol diminished this response (down from 214-fold to 172.4 fold) while Longevinex® further enhanced this microRNA response, from 214-fold to 314.6-fold increase. MicroRNA 539 controls of a number of genes involved in healing heart tissue following a heart attack.