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Zhang Bing’s Team Discovered New Mechanism for Regulating Heart Failure

March 29, 2021      Author:

Heart failure is a complex clinical syndrome. Because the cause of the disease is unclear and there are no effective medicines, the five-year mortality rate of heart failure is around 50%, which is higher than the mortality rate of most cancers. Therefore, it is urgent to clarify its pathogenesis and develop new treatment strategies to deal with this increasingly serious public health problem.

On March 5, 2021, Zhang Bing’s team from Shanghai Center for Systems Biomedicine, SJTU published an article titled “LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis” in Circulation. The team is the first to discover that the RNA-binding protein LARP7 could promote the function of cardiomyocytes to prevent heart failure by regulating mitochondrial biosynthesis and energy metabolism.

LARP7 is a la ribonucleoprotein that binds to the most abundant long-chain non-coding RNA-7SK RNA in mammalian cells. Researchers have observed that LARP7 protein is significantly lower in myocardial tissue in patients with dilated cardiomyopathy (DCM) than in normal human myocardial tissue. The paper aims to study the role and function of LARP7 in myocardial cells and heart diseases.
This study elucidated a new ROS-ATM-LARP7-SIRT1-OXPHOS molecular pathway activated during heart failure. Avoiding excessive activation of this pathway is essential for maintaining mitochondrial biosynthesis, energy metabolism and normal cardiac ejection function.
Yu Hui Jing and Yan Pengyi, the doctoral students of Zhang Bing’s research group, and assistant researchers Zhang Fang and Zhang Shasha are the co-first authors of this article. Researcher Zhang Bing from Shanghai Center for Systems Biomedicine and Xinhua Hospital Affiliated to Shanghai Jiao Tong University is the corresponding author. This work has been supported by the Xinhua Hospital Affiliated to Shanghai Jiao Tong University, SJTU School of Basic Medical Sciences and other teams.

Author: Zhang Bing
Affiliation: Shanghai Center for Systems Biomedicine, SJTU
Translated by: Fu Jing
Proofread by: Xiao Yangning, Fu Yuhe

ABSTRACT:
Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. La ribonucleoprotein domain family member 7 (LARP7) is a master regulator that governs the DNA damage response and RNAPII pausing pathway, but the role of it in heart failure pathogenesis is incompletely understood.
Methods: We assessed LARP7 expression in human HF, and in non-human primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 (AAV9) and ataxia telangiectasia mutated protein (ATM) inhibitor. The therapeutic potential of LARP7-regulated pathways in heart failure was tested in a mouse myocardial infarction model.
Results: LARP7 was profoundly downregulated in failing human hearts and in non-human primate and murine hearts after myocardial infarction (MI). Low LARP7 levels in failing hearts was linked to elevated reactive oxygen species (ROS), which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 stability and deacetylase activity which impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after MI by either AAV-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.
Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts due to activation of the ATM pathway contributes to heart failure pathogenesis, and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in heart failure.