Cardiovascular disease is linked to mysterious genetic material

August 26, 2013 | by

Cardiovascular disease — often stemming from common conditions such as diabetes, hypertension, atherosclerosis and kidney failure — claims about 600,000 U.S. lives each year. It’s the nation’s leading cause of death. Now research led by City of Hope scientists links a little-understood piece of genetic material to the disease — a finding that may point to new therapies.

Close-up image of clinician measuring blood pressure

City of Hope scientists linked long noncoding RNA molecules and angiotensin II, a hormone affecting blood vessel cells. The finding could lead to new treatments for hypertension and cardiovascular disease.

City of Hope researchers studied cells that help form the walls of blood vessels. These cells, called VSMC — short for vascular smooth muscle cells — cause blood vessels to relax or constrict, affecting blood pressure. They’re controlled by the hormone angiotensin II.

Because abnormal production of angiotensin II has been linked to high blood pressure, inflammation and cardiovascular disease, the scientists examined the cells looking for molecules that may be linked to the hormone’s production and action. They found that levels of several different molecules called long noncoding RNAs, or lncRNAs, fluctuate in proportion to levels of angiotensin II.

By finding — for the first time ever — a link between levels of angiotensin II and levels of long noncoding RNA molecules, the scientists open the door to possible new ways of controlling the hormone and the damage it can create when it swings out of control in diabetes and other diseases. That damage ultimately leads to heart disease.

A quick look at RNA
RNA is DNA’s lesser-studied sibling. Historically famous as the middle man helping convert DNA’s genetic instructions into protein, RNA is increasingly coming to light as an agent controlling the activity of genes by various mechanisms. This “noncoding” RNA constitutes a large percentage of the human genome. Scientists have delved deep into studies of small RNA pieces called microRNA and siRNA for years. Now lncRNA — long noncoding RNA — is gaining attention for its role in regulating genes.“They are relatively new players,” said Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research at City of Hope. “Just as we start to understand [microRNAs], we have new players — lncRNAs — to deal with.”Research in this emerging field is accelerating as scientists begin to understand the impact these molecules may have in normal biological processes, disease and aging.

“These lncRNAs could offer a potential therapeutic target to control hypertension,” said Rama Natarajan, Ph.D., National Office Products Industry Professor in Diabetes Research and director of the Division of Molecular Diabetes Research at City of Hope. She is co-senior author on the study with Dustin Schones, Ph.D., assistant professor in City of Hope’s Department of Cancer Biology and an expert in genomics, epigenomics and computational biology.

RNA is a nucleic acid similar to DNA that, among other functions, enables cells to produce proteins. Recent research shows that even RNAs that don’t produce proteins, such as lncRNAs, can have regulatory functions and affect disease processes.

Natarajan said the long noncoding RNAs could lead to treatments for atherosclerosis, the blockage of blood vessels with excess fat, and restenosis, the reblockage of blood vessels following angioplasty.

Amy Leung, Ph.D., a postdoctoral fellow in Natarajan’s lab and the study’s lead author, said the team will continue to look for connections between angiotensin II and other RNA molecules.

The researchers plan to study the newly identified RNA molecules to see what, if any, effects they have in mouse models of diabetes and cardiovascular disease and if they interact with other known risk factors of these diseases, Leung said.

Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under grant numbers R01HL106089, R01HL087864, R01DK065073 and K22HL101950. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.