Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR

Abstract

Background: The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. Methods: We used both gain- and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used to address the role of XBP1s in cell growth in a cell-autonomous manner. Results: We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. Conclusions: Our results reveal a critical role of the XBP1s–FKBP11–mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

“…We first determined whether the HBP enzymes were altered in cultured cardiomyocytes by hypertrophic stimuli in a time course study. Phenylephrine (PE) is an agonist for α1 adrenergic receptor, which is commonly used to stimulate cardiomyocyte hypertrophic growth in vitro [28][29][30] . We isolated and cultured primary neonatal rat ventricular myocytes (NRVMs) from 1 to 2 days old Sprague-Dawley rats as before 9,31 .…”

“…Upon removal of doxycycline from drinking water, tTA was activated and Gfat1 was induced only in cardiomyocytes. We have previously applied this inducible approach in the heart 9,30 , the liver 35 , and the adipose tissue 36 , which represents a tight, efficient, and reproducible means to genetically manipulate gene expression. We supplemented doxycycline (0.1 mg/L) in drinking water during breeding, pregnancy, and weaning.…”

“…Transverse aortic constriction (TAC) surgery. To induce cardiac hypertrophic growth, constriction at the thoracic aorta to the 27-or 28-gauge needle thickness was performed 28,30 . Compared to a 27-gauge needle, constriction to a 28gauge needle led to more severe, decompensated hypertrophy and heart failure 34 .…”

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

“…More recently, it was shown that XBP1 s is protective in a novel murine model of HFpEF via its ability to induce those same proteins involved in O-GlcNAcylation [69]. XBP1 s has an additional role in regulating cardiac hypertrophy in response to pressure-overload via transcriptional induction of FKBP11, and thus regulating mTORC1 activity [94].…”

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

“…Moreover, inhibition of O-GlyNAcases increased mitochondrial OXPHOS enzyme activities, implying that this is one way that O-GlcNAcylation might be protective (35); however, the mechanism by which XBP1-mediated protein O-GlcNAcylation results in cardioprotection remains unclear. In terms of heart failure, it was shown that XBP1s stimulates adaptive cardiac growth through activation of mTORC1, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s, thus describing a non-canonical protective for IRE1/XBP1s in pathological hypertrophy (Figure 2A, IRE1/XBPs cardiac hypertrophy) (36). It has also been shown that in a mouse model of heart failure with preserved ejection fraction (HFpEF), activation of IRE1 is deficient and restoration of activated XBP1 ameliorated the HFpEF phenotype (37).…”