Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis

Abstract

Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.

Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

“…Despite several studies demonstrating the efficacy of ATF6 in mitigating AMI injury, the mechanism of how ATF6, an ER-resident transcription factor, could protect from reperfusion damage associated with AMI or stroke, most of which is caused by oxidative stress and ROS generated by mitochondria, remained elusive. Accordingly, to address this mechanism, recent studies used either a mouse model where ATF6 had been globally deleted (ATF6 KO) [28] or generated a mouse model in which ATF6 is conditionally deleted only in cardiac myocytes (ATF6 cKO) [116]. Transcript profiling of ATF6 transgenic and ATF6 cKO mice revealed that in addition to genes encoding proteins that constitute the ER protein-folding machinery, ATF6 induces genes that encode proteins that do not even reside in the ER.…”

“…As described throughout this review, maintaining cardiac myocyte proteostasis is vital for cellular viability and function, and ATF6 has demonstrated efficacy as a therapeutic target for CVD and cardiac hypertrophy [27,50,116]. Thus, a conceptual framework with specific research approaches was designed in an attempt to identify key proteostasis regulatory pathways via discovering non-canonical gene targets of ATF6 using diverse animal models of various etiologies contributing to CVD.…”

“…Given the robust protection, ATF6 confers during AMI and post-AMI remodeling, the effects of pharmacological activation of ATF6 with 147 in a mouse model of reperfusion damage was chosen for initial efficacy testing [116]. Intravenous administration of 147 concurrently with reperfusion robustly and selectively activated ATF6 and downstream genes of the ATF6 gene program, protected the heart from AMI injury, preserved cardiac function, and decreased infarct size when assessed 24 h after drug administration/reperfusion.…”

Human CardioChimeras: Creation of a Novel ‘Next Generation’ Cardiac Cell

“…NRCMs were isolated as previously described 21,22 and seeded in a 6-well dish at a density of 10 200,000 per well in M199 media with 15% fetal bovine serum (FBS). The following day, cells 11…”

Sorcin stimulates Activation Transcription Factor 6α (ATF6) transcriptional activity

“…ATF6 activation is considered to be the pro-survival branch of the UPR, improving stroke outcomes (53) and myocardial ischemia/reperfusion injury (54,55). In the pancreatic beta cell, ATF6 is needed for beta cell proliferation and compensation during insulin resistance (24) and ATF6-null mice do not display any defects in β-cell function on a normal chow diet but experience severe ER stress with reduced insulin content during HFD (56).…”