Antidiabetic drug metformin for prevention and treatment of atherosclerosis

Atherosclerosis is an inflammatory disease of the arteries that is linked to a very high number of deaths. A new area of interest in the prevention and management of atherosclerosis is autophagy (self-eating), which is the body’s way to clean out damaged cells. Autophagy has a protective effect on the cells in the walls of blood vessels. Absence of autophagy could potentially accelerate aging and cell death. As the name suggests, lncRNAs (long, non-coding RNA) are not associated with protein-encoding. Studies have demonstrated that lncRNAs are closely related to the onset of many forms of heart diseases, including myocardial infarction, heart failure, and atherosclerosis. In particular, dysregulation of the lncRNA TUG1 (taurine upregulated gene 1) has been linked to many diseases including diabetes, stroke, and cancer. The enzyme AMP kinase senses energy and is activated during periods of excess energy use or starvation. AMPK regulates mTOR (mammalian target of rapamycin). AMPK-mediated suppression of mTOR can promote autophagy in various cells in the body. The drug metformin is widely used in the treatment of diabetes. Research has shown that the drug also has a protective effect in cardiovascular diseases, achieved by activating autophagy. Metformin has also been found to suppress cardiac apoptosis (programmed cell death) and has anti-atherosclerosis properties. A study on the role of metformin in atherosclerosis prevention and treatment enrolled 35 individuals with coronary heart disease (CHD). Each of the participants had at least one major coronary artery with at least 80% stenosis (narrowing) diagnosed at the Guizhou Provincial People’s Hospital in Guiyang, China. An additional 38 individuals were enrolled as healthy controls. A laboratory test called qRT-PCR, which is used to quantify gene expression, was employed to detect the expression of TUG1 in blood samples from the CHD patients and healthy controls. The researchers found that TUG1 expression was strikingly upregulated in the CHD patients compared to the healthy controls. Following incubation with metformin for 24, 48, and 72 hours, the scientists observed downregulation of TUG1 in a time-dependent manner. These findings demonstrated that metformin inhibits cell proliferation through autophagy-inducing effects, achieved by increasing the expression of AMPK and decreasing the expression of mTOR. The researchers also demonstrated that knocking down TUG1 expression inhibited proliferation and promoted autophagy, similar to the results with metformin treatment. The lifetime risk of coronary heart disease is nearly 70 percent in people above the age of 55. The widespread occurrence of CHD has prompted scientists to define the functions of lncRNAs, which are vital regulators of atherosclerosis progression. This study demonstrated significant upregulation of lncRNA TUG1 in the peripheral blood of CHD patients compared to healthy individuals, indicating lncRNA TUG1 may be responsible for the progression of coronary heart disease. The mechanism of action of lncRNA TUG1 is through vascular wall cell proliferation and migration and autophagy-mediated through the APMK/mTOR pathway which controls autophagy. Defects in autophagy induce cell proliferation and accelerate atherosclerosis, whereas upregulation of autophagy inhibits the progression of CHD. In the laboratory, metformin was found to attenuate the expression of TUG1 in a time-dependent manner, leading to the possibility that this drug could be used to treat heart diseases through the regulation of lncRNA expression.