Circulation Research “In This Issue” Anthology

Abstract

1 Lin et al reveal how Yes-associated protein activates cardiomyocyte proliferation.Signaling via the Hippo kinase cascade results in the nuclear localization and activation of transcriptional co-activator YAP (Yes-associated protein). The Hippo-YAP pathway promotes cardiomyocyte proliferation in the developing fetal heart and, when over-expressed, in adult cardiomyocytes as well. The transcriptional targets of YAP that control proliferation, however, remain largely unknown. To identify the targets of this pathway, Lin and colleagues performed genome-wide chromatin immunoprecipitation experiments with YAP as well as genome-wide transcriptional profiling of cells that had a gain or loss of function of YAP. The results obtained from these experiments revealed a total of 26 genes that bound directly to YAP (together with its DNA-binding partner, TEAD), and showed increased or reduced transcriptional activity. Among the genes that were upregulated was pik3cb, a gene that encodes part of the catalytic subunit of the kinase PIK3, which has been found in other independent studies to drive cardiomyocyte proliferation. Lin and colleagues went on to show that YAP-induced proliferation required functional pik3cb, and that heart-specific depletion of YAP, which causes hypertrophy and heart failure in mice, could be rescued in part by boosting the expression of pik3cb. Taken together these results indicate that increasing YAP or pik3cb expression could be a useful strategy to stimulate cardiomyocyte proliferation and thereby promote myocardial regeneration after injury. miR-208 in Right Ventricular Failure (p 56) 2Paulin et al identify a right ventricle-specific mechanism in pulmonary hypertension and, with it, potential biomarkers of disease progression.