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Deletion of Cardiomyocyte YAP Potentiates Inflammatory Gene Expression in the Heart
Author(s) -
Brand Cameron S.,
Moon Hoyoung,
Willeford Andrew,
Brown Joan Heller
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07267
Subject(s) - inflammation , fibrosis , cardiac fibrosis , angiotensin ii , knockout mouse , proinflammatory cytokine , rhoa , chemokine , biology , endocrinology , ctgf , downregulation and upregulation , heart failure , medicine , immunology , microbiology and biotechnology , signal transduction , gene , receptor , biochemistry , blood pressure , growth factor
Cardiac inflammation and recruitment of inflammatory cells to the heart are elicited by both ischemic and non‐ischemic injury and precede cardiac fibrosis. Both cardiac and systemic inflammation increases the risk of progression to heart failure. A role for RhoA activation in cardiac fibrosis following non‐ischemic cardiac injury has been demonstrated previously. Our lab and others have documented the importance of transcriptional responses to RhoA activation in the heart, and have shown that this pathway occurs in part through the transcriptional co‐activator Yes‐associated Protein (YAP). Here we tested the hypothesis that YAP and the genes it regulates are involved in generation of inflammatory signals in the cardiomyocyte, which subsequently contribute to recruitment of pro‐inflammatory immune cells. YAP was deleted in the cardiomyocyte compartment by injection of cardiomyocyte‐specific adeno‐associated virus serotype 9 (AAV9) expressing Cre recombinase into adult floxed YAP mice. After 21 days cardiac YAP protein levels were decreased by approximately 50%, with no concomitant decrease of YAP expression in the lung or liver, and without a compensatory increase in expression of the YAP homolog TAZ. Wildtype and YAP knockout mice were then infused with angiotensin‐II (AngII), a GPCR agonist which rapidly induces cardiac inflammation and fibrosis. Hearts were assessed for mRNA levels of various genes after one day of AngII infusion. YAP knockout hearts had attenuated expression of genes associated with cardiac hypertrophy, consistent with previously reported observations. Pro‐inflammatory cytokines and chemokines, including CCL2 , IL‐6 , and IL‐1β were upregulated in hearts from wildtype mice infused with AngII. Surprisingly these transcriptional responses, when assessed after one day of AngII infusion, were enhanced in hearts from YAP knockouts. We previously reported that pro‐inflammatory gene expression is increased in the heart after three hours of AngII infusion, a time at which macrophage recruitment to the heart has not yet occurred. Interestingly, in contrast to what we observed at one day of AngII, we determined that inflammatory gene expression was not potentiated in YAP knockouts at three hours of AngII. These data suggest that loss of cardiomyocyte YAP may enhance inflammation by increasing recruitment or activation of pro‐inflammatory immune cells, rather than directly affecting inflammatory gene expression in cardiomyocytes. We are currently investigating the relative contribution of cardiomyocytes and non‐cardiomyocytes to inflammatory gene expression by using isolated cell fractions. In summary, we propose that YAP dependent signaling in the cardiomyocyte suppresses inflammatory gene expression in response to AngII through release of factors that decrease macrophage recruitment or activation. Future studies will investigate YAP dependent transcriptional targets through which cardiomyocytes signal to regulate inflammatory responses. Support or Funding Information This work is supported by AHA fellowship 19POST34430051 (CSB), and NIH grant R37HL028143 (JHB).