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Discovery and gene therapy treatment of a novel heart failure mechanism

October 11, 2016

A key protein that causes heart failure has been revealed through new research from a collaboration based in Kumamoto University, Japan. The protein ANGPTL2 (Angiopoietin-like protein 2) is secreted by cardiac muscle cells and decreases the contraction force of the heart by reducing energy production and the regulating function of the calcium concentration in cardiac muscle cells. Utilizing gene therapy to inhibit the production of ANGPLT2, researchers were able to produce beneficial therapeutic effects in both a heart failure mouse model and in human cardiac muscle cells which were differentiated from iPS cells.

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.

Professor Yuichi Oike's research team 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," said Professor Oike. "Furthermore, we genetically engineered a non-pathogenic virus which was designed to infect cardiac muscle cells and reproduce a special RNA molecule that inhibit 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 iPS 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.
-end-
These findings were published online in Nature Communications on Sept. 28th 2016.

[Citation]

Z. Tian, et al., "ANGPTL2 Activity in Cardiac Pathologies Accelerates Heart Failure by Perturbing Cardiac Function and Energy Metabolism," Nat. Commun., vol. 7, p. 13016, Sep. 2016. DOI: 10.1038/ncomms13016.

Kumamoto University

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