ER stress induces upregulation of transcription factor Tbx20 and downstream Bmp2 signaling to promote cardiomyocyte survival

In the mammalian heart, fetal cardiomyocytes proliferate prior to birth; however, they exit the cell cycle shortly after birth. Recent studies show that adult cardiomyocytes re-enters the cell cycle postinjury to promote cardiac regeneration. The endoplasmic reticulum (ER) orchestrates the production and assembly of different types of proteins, and a disruption in this machinery leads to the generation of ER stress, which activates the unfolded protein response. There is a very fine balance between ER stress-mediated protective and proapoptotic re-sponses. T-box transcription factor 20 (Tbx20) promotes em-bryonic and adult cardiomyocyte proliferation postinjury to restore cardiac homeostasis. However, the function and regu-latory interactions of Tbx20 in ER stress-induced cardiomy-opathy have not yet been reported. We show here that ER stress upregulates Tbx20, which activates downstream bone morphogenetic protein 2 (Bmp2)-pSmad1/5/8 signaling to induce cardiomyocyte proliferation and limit apoptosis. How-ever, augmenting ER stress reverses this protective response. We also show that increased expression of tbx20 during ER stress is mediated by the activating transcription factor 6 arm of the unfolded protein response. Cardiomyocyte-specific loss of Tbx20 results in decreased cardiomyocyte proliferation and increased apoptosis. Administration of recombinant Bmp2 protein during ER stress upregulates Tbx20 leading to augmented proliferation, indicating a feed-forward loop mechanism. In in vivo ER stress, as well as in diabetic cardio-myopathy, the activity of Tbx20 is increased with concomitant increased cardiomyocyte proliferation and decreased apoptosis. These data support a critical role of Tbx20-Bmp2 signaling in promoting cardiomyocyte survival during ER stress-induced cardiomyopathies.

Automated summary

In the mammalian heart, fetal cardiomyocytes proliferate prior to birth and adult cardiomyocytes re-enter the cell cycle postinjury to promote cardiac regeneration. Disruption of the endoplasmic reticulum (ER) machinery leads to ER stress, which has a fine balance between protective and proapoptotic responses. T-box transcription factor 20 (Tbx20) is upregulated in ER stress and promotes cardiomyocyte proliferation and limits apoptosis.