GPER Knockout Reduces Oxidative Stress to Slow Cardiovascular Aging

In the research noted below, scientists report on the discovery that loss of the GPER gene can slow the pace at which cardiovascular disease progresses, albeit only modestly. Since the molecular biochemistry of a cell is so intertwined, and any given mechanism can be influenced by the presence or absence of numerous different proteins, the existence of any one demonstration of this nature means that should expect there to be a fair number of genes and proteins that might have similar effects if manipulated. Equally, we should also expect most to have only small effects, or to also have unwanted side-effects that make them unsuitable targets for comparatively blunt and sweeping operations such as gene knockout. Most proteins have numerous different roles in cellular processes, which makes it rare to find one that can be removed entirely. Thus the real interest occurs when it is demonstrated that a gene can indeed be done away with without ill effects, an entirely beneficial change - as is the case for PCSK9, mentioned yesterday, among others.

Considering the existence of beneficial mutations, one has to concede that evolution has gifted mammals with a genome that is suboptimal in many ways. Researchers have discovered single gene alterations that increase muscle mass, improve cellular housekeeping, make metabolism work better over the long term, reduce cardiovascular disease, and so forth. That these single gene alterations are there to be developed into a near future of enhancement gene therapies is one of many indications that evolutionary fitness doesn't correspond all that well to individual advantage. Natural selection favors an inferior model, or at least inferior when considered from the vantage point of being someone who is stuck with a body and biochemistry laboriously produced in this manner. Aging itself is the largest of our problems, and may well result from an evolutionary arms race to the bottom; one view of the evolutionary theory has it that aging helps species adapt to changing environments, and since the world does indeed change, the result is that near every present and historical species is made up of individuals who age to death. The immortals were out-competed, save for a few remnants here and there, such as hydra.

Researcher Discovers New Class of Drugs to Combat Aging Diseases

G protein-coupled estrogen receptor, or GPER, determines in part how our cells respond to the hormone estrogen and to estrogen-like substances. GPER plays a role in diseases like breast cancer and diabetes, but also mediates many beneficial functions in physiology. Researchers found that making GPER more active in mice placed on a high fat diet reduced the development of atherosclerosis, a condition in which the blood vessels harden and narrow. But another study's results with old mice were a surprise. The researchers observed mice that lacked GPER in all their cells as they aged. They tracked the mice over the normal mouse life span of about two years. They expected these mice to show increased levels of aging-related disease in their hearts and blood vessels. Instead, compared with normal aged mice, the GPER-lacking mice had healthier hearts and blood vessels. The team then conducted a series of experiments to learn why. They discovered an altered balance between certain signaling molecules in the smooth muscle cells of blood vessels and the heart.

One of those signaling molecules, superoxide, is a type of reactive oxygen species. Reactive oxygen species react quickly and strongly with nearby cellular proteins and impede those proteins' ability to perform their tasks. Over time, the cell's proteins and other components degrade enough to prevent normal cell functions. Almost every disease of aging is influenced by reactive oxygen species. The researchers next tested whether a GPER-blocking drug would improve smooth muscle cell function, as they observed in cells lacking GPER. They discovered that blocking GPER changed how the blood vessels' smooth muscle cells expressed their genes. One of the genes that the drug affected produces a protein called NOX1. NOX1 produces superoxide, one of the most reactive molecules the body produces. By blocking GPER, the team's drug also blocked NOX1 expression, reducing the amount of superoxide the cell produced and reducing cellular aging. The blood vessels of people, and mice, with chronic diseases like diabetes, heart disease and cancer show signs of accelerated aging. By preventing NOX1 expression to block a cell from producing excess superoxide, researchers hope to find a treatment for these conditions one day.

Obligatory role for GPER in cardiovascular aging and disease

Ligand-dependent activation of the G protein-coupled estrogen receptor (GPER) has been reported to confer cardiovascular benefits. However, we found that genetic absence of Gper conferred protection from cardiovascular pathologies associated with aging and hypertension. GPER activity was required to increase the abundance of the enzyme Nox1 in vascular smooth muscle cells, blood vessels, and myocardium, and was associated with enhanced production of tissue-damaging superoxide. Aged mice that were deficient in Gper developed much less cardiac fibrosis and hypertrophy and also retained greater cardiovascular function. In addition, a pharmacological inhibitor of GPER reduced blood pressure, superoxide production, and Nox1 abundance in hypertensive mice. Thus, inhibitors of GPER are potential therapies for cardiovascular diseases and conditions characterized by excessive superoxide generation. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive superoxide formation, including arterial hypertension and heart failure.

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