Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts

Abstract

Heart failure is the leading cause of morbidity and mortality worldwide. Several lines of evidence suggest that physical activity and exercise can pre-condition the heart to improve the response to acute cardiac injury such as myocardial infarction or ischemia/reperfusion injury, preventing the progression to heart failure. It is becoming more apparent that cardioprotection is a concerted effort between multiple cell types and converging signaling pathways. However, the molecular mechanisms of cardioprotection are not completely understood. What is clear is that the mechanisms underlying this protection involve acute activation of transcriptional activators and their corresponding gene expression programs. Here, we review the known stress-dependent transcriptional programs that are activated in cardiomyocytes and cardiac fibroblasts to preserve function in the adult heart after injury. Focus is given to prominent transcriptional pathways such as mechanical stress or reactive oxygen species (ROS)-dependent activation of myocardin-related transcription factors (MRTFs) and transforming growth factor beta (TGFβ), and gene expression that positively regulates protective PI3K/Akt signaling. Together, these pathways modulate both beneficial and pathological responses to cardiac injury in a cell-specific manner.

Keywords: Cardioprotection; cardiac fibroblast; cardiomyocyte; exercise; transcription.

Figure 1

Signaling pathways that modulate cardioprotection in CMs. Mechanical and oxidative stress produced in disease or exercise can induce a complex anti-apoptotic and hypertrophic response in CMs that converges on the RhoA and PI3K/Akt signaling pathways. Stimulation of GPCRs through ligands triggers RhoA-dependent actin polymerization and nuclear localization of MRTFs to activate transcription of MRTF/SRF target genes. Expression of targets such as miR-486 and CCNs, as well as exercise-induced mechanical tension can activate the Akt response to contribute to cardioprotection. RhoA can also modulate the Hippo/YAP signaling pathway to regulate proliferation and stress responsive genes during both development and disease.

Figure 2

Signaling pathways that contribute to CF activation and stress response. Disease or mechanical stress can stimulate multiple pathways including calcineurin (Cn)/NFAT, TGFβ, GPCR, and EGFR signaling. The TGFβ pathway provides an established mechanism to stimulate SMAD-dependent CF activation and fibrosis. RhoA/MRTF-dependent signaling plays a central role in CF activation through the non-canonical TGFβ pathway, GPCR stimulation, or EGFR activation. Inhibition of TGFβ signaling by Y-27632 or Fasudil treatment, or by repressive SMAD6/7 signaling, provide nodes to control CF activation. CF activation may also be modulated through epigenetic modulation such as pharmacological inhibition of HDAC-1 or BRD4. Finally, exercise can increase mechanical load in the absence of fibrosis, potentially by maintaining an antioxidant response regulated by NRF2.