Suppressing ANGPTL2 Slows the Progression of Heart Failure
Researchers here present a potential way to slow the progression of heart failure. They have identified one of the proximate causes of pathology, a change in the gene expression of ANGPTL2 that accompanies aging or damage in heart tissue. Suppressing this signal improves function and slows the decline. This, like many of today's potential therapeutic approaches, is compensatory in nature. It doesn't address the underlying reasons for the identified change, but seeks to adjust the behavior of damaged tissues to be more youthful despite that damage. It cannot fix the problem, it can only slow down the inevitable; arguably other approaches that do address the root cause damage should have a higher priority.
Heart failure occurs when heart function is reduced making it no longer able to pump enough blood to body. Patients with severe heart failure have a very poor prognosis, with a five-year survival rate of 50-60% despite advances in modern medicine and medical technology. Researchers found that cardiac muscle cells that were from heart failure patients, were aged cells, or were under the stress of high blood pressure had increased production and secretion of the protein ANGPTL2. The research team previously reported that excessive secretion of the ANGPTL2 protein by aged or stressed cells causes chronic inflammation and promotes the development of lifestyle-related diseases such as atherosclerotic disease, obesity, diabetes, or cancer. ANGPTL2 is also related to heart failure. Excessive ANGPTL2 secretions by cardiac muscle cells impair important functions, such as intracellular calcium concentration regulation and energy production, that help maintain the contractile force of the heart. On the other hand, moderate exercise reduces the production of ANGPTL2 in cardiac muscle cells which helps keep the heart healthy.
"We found that ANGPLT2 is significantly involved in heart failure. Among knockout mice that could not produce the protein, the development of heart failure was suppressed in a manner similar to moderate exercise. Furthermore, we genetically engineered a non-pathogenic virus which was designed to infect cardiac muscle cells and reproduce a special RNA molecule that inhibited the production of the ANGPTL2 protein." This new gene therapy in the heart failure mouse model was successful in suppressing ANGPTL2 production in cardiac muscle cells thereby reducing the pathological progression of heart failure. Additionally, in cardiac muscle cells that were differentiated from human induced pluripotent stem cells, the suppression of ANGPYL2 promoted calcium concentration regulation and enhanced energy production. It is considered that the newly developed gene therapy may also be effective for human heart failure patients. Current treatment for heart failure is mainly symptomatic. The gene therapy developed here is expected to become a fundamental treatment that corrects the mechanism of reduced heart function itself.