A sequence of genetic material called miR-33a helps keep high-density lipoprotein (HDL, the "good" cholesterol) at a stable level, scientists have discovered.
MiR-33a is a "micro" ribonucleic acid (microRNA) within the gene SREBF-2, which helps regulate cholesterol uptake and synthesis. Researchers found that miR-33a in mice and nonhuman primates is regulated by dietary cholesterol. MicroRNAs are small RNAs that often help regulate cellular processes by suppressing RNA expression – serving as an "off" switch, or an inhibitor, to certain genes.
While investigating what biological activities miR-33a targets, researchers found that it inhibits the production of two types of proteins — ABCA1 and ABCG1 — that transport cholesterol across cell membranes. MiR-33 inhibition of the two ATP binding cassette transporters can reduce circulating HDL. MiR-33a can also repress the expression of a protein called Neimann-Pick C1, which is involved in the transport of cholesterol inside cells and helps move cholesterol to ApoA1.
Silencing miR-33a in macrophages (immune system cells that fight infection and promote atherosclerosis) and liver cells will increase HDL.
In collaboration with Regulus Therapeutics, a company developing microRNA-based therapeutics, the authors tested the potential of inhibiting miR-33 for HDL-raising drug therapy. The researchers gave either doses of anti-miR-33a or control anti-miR for four weeks to mice with established coronary artery disease. The mice that received anti-miR-33a had a 36 percent increase in HDL in their blood compared to the control mice, which was statistically significant.
Moreover, researchers found that mice treated with anti-miR33a had regression of existing atherosclerosis, with 35 percent smaller lesions in anti-miR33 treated mice compared to controls.
The finding suggests a possible approach to increasing HDL in humans as a therapeutic target for coronary artery disease.
Katey Rayner, Ph.D., and Kathryn Moore, Ph.D., New York University Medical Center, New York, N.Y.; (212) 263-2235; katey.rayner@nyumc.org.
(Note: Actual presentation time is 2:30 p.m. CT, Tuesday, Nov. 16, 2010.)
Abstract 19753/P5011 – Novel biopolymer hydrogel reduces left ventricle damage in moderately to severely disabled heart failure patients
In a German study, heart size and function and quality of life improved in heart failure patients treated by implanting an innovative biopolymer into their damaged left ventricles.
The improvements were maintained for at least three months, researchers said.
The first-in-man prospective safety and feasibility evaluation of Algisyl-LVR, an injectable biopolymer hydrogel, involved six heart failure patients. A hydrogel consists of long-chain molecules that have entrapped many times their weight in water.
Researchers sought to reduce heart-wall stress and prevent or reverse harmful changes in a damaged ventricle's size, shape and function by injecting the hydrogel when the patients had an artery bypass or heart valve operation.
During surgery, the researchers also treated the six patients (four with ischemic and two non-ischemic with dilated cardiomyopathy) with Algisyl-LVR injections. The patients had moderate or severe disability and received 10 to 15 injections, at 0.3 centimeters of the hydrogel per shot, into the left ventricle wall.
Researchers evaluated participants at three days, eight days and three months after treatment. Improvements in left ventricle size and function were seen in all patients as early as three days after surgery.
The patients showed sustainable improvement in ventricle size and function at the three-month follow-up. They also demonstrated statistically significant enhancement in clinical status and quality of life.
The trial indicated a satisfactory tolerability and safety profile in patients and favored continued clinical development of the biopolymer, researchers said.
Beatrice Retzlaff, M.D., German Heart Center, Munich, Germany; (011) 49-89-1218-3701; bretzlaff@live.de; Mobile: 0049-177-3716872.
(Note: Actual presentation time is 9:30 a.m. CT, Monday, Nov. 15, 2010)
Abstract 21346 – Tissue engineering may lead to hybrid hydrogels to repair heart damage
An advanced tissue-engineering concept may lead to a new class of injectable, biologically active hydrogels to repair heart muscle damage caused by heart attacks, researchers said.
A hydrogel consists of long-chain molecules that have entrapped many times their weight in water. Tissue-engineering strategies for replacing damaged heart tissue focus on new cells or bioactive materials.
The study is a collaboration between biophysicists, biomedical engineers and cardiac surgeons at the University of Pennsylvania and at Drexel University College of Medicine in Philadelphia. They examined how a new material designed by a biotechnology company may optimize the response of heart muscle cells (myocytes) by growing them with proteins like those in the extracellular matrix (ECM), an interlocking mesh of fibrous proteins and connective tissues that provide support for cells.
Researchers cultured neonatal rat myocytes on two gel systems of various stiffness — polyacrylamide (PA) and HyStem — that were modified with adhesion proteins from the native cardiac ECM. After 48 hours, the cells were fixed and stained to visualize the proteins F-actin, α-actinin and vinculin, which are involved in various ways with heart muscle activity.
Surprisingly, muscle cell structure and contraction increased 105 percent in myocytes grown on a relatively soft HyStem system, researchers said. The cells were also highly preserved compared to myocytes grown on a PA system of similar stiffness.
J. Yasha Kresh, Ph.D., Drexel University College of Medicine, Department of CT-Surgery, Philadelphia, Pa.; (215) 762-1703; jkresh@drexelmed.edu; Anant Chopra, (215) 762-3461; ac429@drexel.edu.
(Note: Actual presentation time is 4:45 p.m. CT, Monday, Nov. 15, 2010.)
Abstract 16273 — Treatment with stem cell "spheres" improves heart attack damage in mice
Adult stem cells that are grown to cluster in spherical structures survive and improve heart function better than stem cells grown as single cells or in cell sheets when implanted in mice after a heart attack. The findings herald a potential new approach to treating heart patients.
The stem cells and their supporting cells and molecules were obtained from biopsied human endomyocardial tissue - the layer of tissue and muscle lining the inside of the heart's chambers. Researchers grew cells in 3-D structures known as cardiospheres and as cellular sheets, or monolayers, that are one-cell thick.
The cardiospheres showed significantly higher levels of transcription factors and chemicals vital to the growth and self-renewal of stem cells (C-kit+, SOX2, and Nanog) compared to the layered stem cells. In mice injected with human cells, the cardiospheres resulted in more cell "engraftment" (the stem cells incorporating into the animals' hearts) and improved heart function compared to monolayer-grown single stem cells.
The scientists concluded that cardiac stem cell survival and potency for heart repair is stronger with cardiospheres than monolayer stem cells.
Eduardo Marban, MD, Ph.D., Cedars-Sinai Heart Institute, Los Angeles, Calif. (310) 248-6566; eduardo.marban@csmc.edu; or via Sally Stewart at (310) 729-4369; sally.stewart@cshs.org.
(Note: Actual presentation time is 3 p.m.CT, Tuesday, Nov. 16, 2010.)
Also see: Abstract 20957 (2:30 p.m.) for a comparison of human cardiosphere-derived cells to three other kinds of stem cells: mesenchymal stem cells, adipose-derived stem cells and bone marrow mononuclear cells. And: Abstract 19030 (2:15 p.m. CT) for an animal study of the effect of cardiospheres after heart attack in subjects with heart failure.
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