Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy

Abstract

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. Methods: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. Conclusions: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.

Left Ventricular Hypertrophy and Hypertrophic Cardiomyopathy in Adult Solid Organ Transplant Recipients

“…In their series, the 5 patients with HCM and echocardiographic LVOT obstruction were all renal transplant recipients, and 4 of 5 had a history of hypertension. The pathogenesis of tacrolimus-associated HCM has been attributed to increases in calcium release, which subsequently activate signaling pathways that prompt cardiac hypertrophy 25 ; however, the totality of mechanisms involved in hypertrophic myocardial growth remain under active investigation 26 (Figure 2 ). Prospective characterization of LV size, wall thickness, and mass in adult solid organ transplant recipients as part of routine posttransplant care may be a high-yield strategy for future discovery and mitigation of symptoms and cardiopulmonary limitation.…”

Phosphoproteomic Analysis Reveals Downstream PKA Effectors of AKAP Cypher/ZASP in the Pathogenesis of Dilated Cardiomyopathy

“…Moreover, sequence analysis showed a strong predilection for motif sequence SP in Groups 2 and 3 ( Figures 3C,D ), a hallmark of GSK-3, MAPK, and CDK substrates ( 19 ). Accumulating evidence suggests that MAPKs play a key role in the development of DCM ( 41 , 42 ). The phosphorylation of MAPKs, such as ERK, P38, and MEK3/6, has been shown to be dramatically altered in Cypher-KO mice ( 8 ), which strongly supports the efficiency of our proteomic analysis.…”

Transcription Factors Involved in the Development and Prognosis of Cardiac Remodeling

“…Furthermore, overexpression of calcineurin leading to constitutive activation of NFAT dramatically increases the expression of BNP transcripts and induces serious cardiac hypertrophy and fibrosis in mice. In addition to Nppb, regulator of calcineurin 1.4 is validated as a direct target of NFAT in NRVMs (Luo et al, 2021). Recently, the role of NFAT in epigenetics was noted.…”

“…Recently, the role of NFAT in epigenetics was noted. NFAT controls many microRNAs transcription, such as miR-23a and miR-223 (Luo et al, 2021). These microRNAs controlled by NFAT are positively correlated with pathological cardiac hypertrophy (Chen et al, 2017).…”