In a new Yale-led study, investigators have revealed previously unknown factors that contribute to the hardening of arteries and plaque growth, which cause heart disease. Their insight is the basis for a promising therapeutic approach to halt and potentially reverse plaque buildup and the progression of disease, the researchers said.
Treatments for plaque and arteries
Current treatments for plaque and harden arteries; so a condition known as atherosclerosis; can slow but not improve the disease. Experts believe that may be due to ongoing inflammation in blood vessels. To understand the factors contributing to this inflammation; So the research team focus on a group of proteins, called transforming growth factor beta (TGFß); that regulates a wide range of cells and tissues throughout the body.
Atherosclerosis is a progressive vascular disease trigger by interplay between; abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall; which is thought to be responsible for disease progression characterize by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined.
Using culture human cells, the researchers discover that TGFβ proteins trigger inflammation in endothelial cells the cells that form the inner lining of artery walls but not in other cell types. With a technique called single cell RNA-seq analysis; which measures the expression of every gene in single cells; they then show that TGFβ induce inflammation in these cells. This finding was notable, said the researchers; so because TGFβ proteins are known to decrease inflammation in other cells in the body.
Approach of potential therapy
The researchers also show that when the TGFβ receptor gene is delete in endothelial cells; both the inflammation and plaque in blood vessels are significantly reduce. To test this approach as a potential therapy, the team; led by professor of medicine Michael Simons, M.D., use an “interfering” RNA, or RNAi, drug develop at Yale, to disrupt TGFß receptors.
Interfering RNA use a gene’s own DNA sequence to turn off or silence the gene. To deliver the drug only to endothelial cells in the blood vessel walls of mice; they employ microscopic particles, or nanoparticles, create by their co-authors at MIT. This strategy reduce inflammation and plaque as effectively as the genetic technique.
The findings identify TGFß signaling as a major cause of chronic vessel wall inflammation; also demonstrate that disruption of this pathway leads to cessation of inflammation and substantial regression of existing plaque, said the scientists. Base on this discovery, investigators at Yale and MIT have launch a biotech company, VasoRX, Inc. To develop this target approach; using the RNAi drug deliver by nanoparticles as a potential therapy for atherosclerosis in people.