Researchers Uncover a Critical Role of the Hippo Pathway in the Heart’s Natural Pacemaker
A collaborative research team spearheaded by Dr. Jun Wang, Associate Professor in the Department of Pediatrics at McGovern Medical School of The University of Texas Health Science Center at Houston (UTHealth Houston) and member of The Texas Heart Institute Professional Staff, showed for the first time that the canonical Hippo-Yap signaling pathway plays a pivotal role in regulating sinoatrial node homeostasis. These findings have been recently published in Circulation. Dr. Wang is the corresponding author of the paper, Dr. Mingjie Zheng at UTHealth Houston is the first author, and Drs. Rich Li and Xiao Li at The Institute are co-authors.
The sinoatrial node is the heart’s natural pacemaker, initiating and maintaining rhythmic heartbeats. When the sinoatrial node does not function properly, the electrical impulses of the heart can become abnormal and cause irregular heartbeats (arrhythmias). This condition is referred to as sinus node dysfunction, and its incidence increases with age and other risk factors. As the incidence of sinus node dysfunction continues to rise, understanding the molecular machinery that controls the sinoatrial node is of considerable interest.
“The canonical Hippo signaling pathway is a fundamental pathway that has been shown to play key roles in heart development and regeneration. In humans, abnormalities in the Hippo signaling pathway have been associated with cardiac arrhythmias, but the role of this pathway in the sinoatrial node was previously unknown,” explains Dr. Wang. When Hippo signaling is turned on, two major components of the canonical Hippo pathway—kinase enzymes Lats1 and Lats2—act to modify the downstream proteins Yap and Taz and promote their degradation. When Hippo signaling is turned off, Yap and Taz can translocate into cell nuclei to regulate the expression of specific genes. By performing comprehensive studies with various mouse models and cutting-edge techniques, the researchers found that the canonical Hippo-Yap/Taz signaling pathway is required for normal sinoatrial node function and regulates the expression of genes important for cardiac conduction.
Importantly, the researchers found that when the key Hippo signaling components Lats1 and Lats2 were missing from the cardiac conduction system of mice, these mice developed cardiac conduction disorders such as sinoatrial node dysfunction. In addition, calcium homeostasis in the sinoatrial node was disrupted, and the formation of fibrotic tissue (fibrosis) in the sinoatrial node was increased. The researchers also showed that the deletion of the genes encoding Yap and Taz can prevent the cardiac conduction disorders caused by missing Lats1 and Lats2, indicating that Lats1 and Lats2 function through the canonical Hippo-Yap signaling pathway in the sinoatrial node.
When the researchers further examined gene expression in the heart of mice without the Hippo signaling pathway components Lats1 and Lats2, they found that the expression of genes critical for sinoatrial node function was altered. For example, the expression of genes important for pacemaker cell function was reduced, whereas the expression of genes important in fibrosis induction was increased. This suggested that the sinoatrial node dysfunction observed in these mice resulted from the absence of canonical Hippo signaling that may be necessary to properly regulate gene expression in the sinoatrial node.
“Our physical findings in the mouse heart were consistent with our observations made at the molecular level, all pointing to the canonical Hippo-Yap signaling pathway playing a vital role in sinoatrial node homeostasis. Because the Hippo pathway is highly conserved between mice and humans, these insights are likely to be applicable for developing new therapeutic targets in the treatment of patients with heart conduction disorders,” concludes Dr. Wang.
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Zheng M, Li RG, Song J, Zhao X, Tang L, Erhardt S, Chen W, Nguyen BH, Li X, Li M, Wang J, Evans SM, Christoffels VM, Li N, Wang J. Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis. Circulation. 2022 Nov 29;146(22):1694-1711. doi: 10.1161/CIRCULATIONAHA.121.058777. Epub 2022 Nov 1. PMID: 36317529.
Figure. The canonical Hippo signaling pathway is required for normal sinoatrial node function and regulates the expression of genes important for cardiac conduction. ECM, extracellular matrix; SR, sarcoplasmic reticulum.
News Story By Nicole Stancel, PhD, ELS(D)
