Transcriptional pathways and potential therapeutic targets in the regulation of Ncx1 expression in cardiac hypertrophy and failure

Abstract

Changes in cardiac gene expression contribute to the progression of heart failure by affecting cardiomyocyte growth, function, and survival. The Na(+)-Ca(2+) exchanger gene (Ncx1) is upregulated in hypertrophy and is often found elevated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. Several transcriptional pathways mediate Ncx1 expression in pathological cardiac remodeling. Both α-adrenergic receptor (α-AR) and β-adrenergic receptor (β-AR) signaling can play a role in the regulation of calcium homeostasis in the cardiomyocyte, but chronic activation in periods of cardiac stress contributes to heart failure by mechanisms which include Ncx1 upregulation. Our studies have even demonstrated that NCX1 can directly act as a regulator of "activity-dependent signal transduction" mediating changes in its own expression. Finally, we present evidence that histone deacetylases (HDACs) and histone acetyltransferases (HATs) act as master regulators of Ncx1 expression. We show that many of the transcription factors regulating Ncx1 expression are important in cardiac development and also in the regulation of many other genes in the so-called fetal gene program, which are activated by pathological stimuli. Importantly, studies have revealed that the transcriptional network regulating Ncx1 expression is also mediating many of the other changes in genetic remodeling contributing to the development of cardiac dysfunction and revealed potential therapeutic targets for the treatment of hypertrophy and failure.

Figure 11.1

Agonist-specific regulation of Ncx1. β-AR agonist isoproterenol (1 µM) or dobutamine (1 µM) activates CaMKinase II which then activates JunB and c-Jun, which sequentially binds to AP-1 elements and activates Ncx1 expression. α-AR agonist phenylephrine (10 µM) activates SRF via MAP kinase-p38 activation. SRF binds to CArG elements and mediates Ncx1 upregulation. HDACs regulate Ncx1 via the NKE element by deacetylating Nkx2.5. Inhibition of NCX1 by its reverse mode inhibitor KB-R7943 activates Ncx1 upregulation via activating MAP kinase p38 pathway

Figure 11.2

Regulation of Ncx1 gene by HDAC’s. Model for the role of acetylation in Ncx1 transcriptional regulation. We speculate that the Ncx1 promoter cycles through at least four kinetic steps. Step 1: Acetylated Nkx2.5 recruits HDAC5, HDAC1, and HDAC2 complex to the promoter. The presence of the HDAC complex allows for low levels of Ncx1 expression. Step 2: When the HDAC complex deacetylates Nkx2.5, HDAC5, HDAC1, and HDAC2 dissociate from the promoter and the HAT, p300, is recruited to the promoter. Step 3: p300 and its associated coactivators stabilize the Poll II complex to allow a high level of transcription of the Ncx1 gene. Step 4: When p300 acetylates Nkx2.5, it dissociates from the promoter and HDAC5, HDAC1, and HDAC2 are recruited to the promoter. Importantly, TSA treatment traps the Ncx1 promoters in the low transcriptional state. HDAC5 is not itself a coactivator, but deacetylation of Nkx2.5 is required for the recruitment of activators to the Ncx1 promoter in response to hypertrophic stimuli