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Novel Roles for Activating Transcription Factor 6 α in the Activation and Differentiation of Cardiac Non-myocytes


Numerous stresses on the heart, both physiological and pathological, present challenges to ER proteostasis in the heart. Simultaneously, various cardiac cell lineages respond to injury in ways requiring increased protein flux through the ER. While cardiac myocytes react to these stresses largely through hypertrophy or cell death mechanisms, other non-myocyte cells in the heart respond in more dynamic ways, including proliferation and differentiation. Additionally, virtually all cardiac cells secrete signaling cytokines or hormones both at baseline and during injury. Thus, precisely when ER proteostasis is most critical, cells are challenged with conditions which impair ER protein folding. ER unfolded protein response signaling attempts to respond to these challenges through the three main ER stress sensors, PERK, IRE1, and ATF6α. All sense protein misfolding and induce downstream signaling which, to varying degrees, includes global translational attenuation with concurrent upregulation of chaperones, protein disulfide isomerases, and ER-associated degradation machinery. Of these pathways, ATF6α is the most extensively characterized as adaptive in the heart and other tissues. Additionally, recent studies have identified multiple noncanonical ATF6α gene programs which are only indirectly related to ER proteostasis but are nevertheless critical to the ability of ATF6α to preserve tissue function. Research on the effect of ATF6α in the heart had previously been restricted to ventricular myocytes. Though these cells are the most direct effectors of cardiac function, this ignores critical roles played by other cardiac non-myocyte cells. This work examines the effects of ATF6α gain- and loss-of-function in three model systems designed to uncover previously unknown roles for ATF6α signaling in cardiac non-myocytes. ATF6α global knockout mice were found to progress to heart failure more quickly than wild-type counterparts following permanent-occlusion myocardial infarction, an unexplored disease model in the context of ATF6α signaling. We subsequently explored the role of ATF6α in two murine cardiac non-myocyte cell types. The first, c-Kit+ cardiac stem cells, required ATF6α both for survival and stemness while ATF6α loss-of-function induced multiple lineage markers. Second, we identified roles for ATF6α in limiting fibrosis in a pressure overload injury model and found that ATF6α blunted activation of isolated adult murine ventricular fibroblasts.

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