Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

Abstract

Cardiac hypertrophy is the result of increased myocardial cell size responding to an increased workload and developmental signals. These extrinsic and intrinsic stimuli as key drivers of cardiac hypertrophy have spurred efforts to target their associated signaling pathways. The extracellular signal-regulated kinases 1/2(ERK1/2), as an essential member of mitogen-activated protein kinases (MAPKs), has been widely recognized for promoting cardiac growth. Several modified transgenic mouse models have been generated through either affecting the upstream kinase to change ERK1/2 activity, manipulating the direct role of ERK1/2 in the heart, or targeting phosphatases or MAPK scaffold proteins to alter total ERK1/2 activity in response to an increased workload. Using these models, both regulation of the upstream events and modulation of each isoform and indirect effector could provide important insights into how ERK1/2 modulates cardiomyocyte biology. Furthermore, a plethora of compounds, inhibitors, and regulators have emerged in consideration of ERK, or its MAPKKs, are possible therapeutic targets against cardiac hypertrophic diseases. Herein, is a review of the available evidence regarding the exact role of ERK1/2 in regulating cardiac hypertrophy and a discussion of pharmacological strategy for treatment of cardiac hypertrophy.

Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer

“…Regulator of G Protein Signaling 14 ( RGS14 ) is a protein coding gene that plays a role in the signaling by GPCR and Ras signaling pathway, as well as serving as an inhibitor of platelet-derived growth factor (PDGF)-stimulated ERK1/ERK2 phosphorylation. This gene has been implicated in cardiovascular disease and has been shown to play a role in cardiac remodeling [ 45 , 46 ]. The protein coding gene, Kelch Like Family Member 31 ( KLHL31 ) inhibits the transcriptional activities of TPA-response element (TRE) and serum response element (SRE).…”

Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes

“…Indeed, numerous studies have shown that Akt positively regulates physiological heart growth [ 36 , 37 ]. Cardiomyocyte hypertrophy is also orchestrated by MAP signaling kinases, with Erk1/2 activation being assigned to both physiological and pathological types of hypertrophy [ 38 , 39 , 40 ], and Jnk and p38 kinases being characteristic for stress-induced pathological hypertrophy [ 26 ].…”

Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

“…Several studies have shown that cardiac hypertrophy can be induced by the activation of multiple signaling pathways ( 5 – 8 ). The extracellular signal-regulated protein kinase (ERK) signaling pathway is considered to play a particularly important role in regulating pathological cardiac hypertrophy ( 9 – 11 ). Our previous study demonstrated that the HAT inhibitor, anacardic acid (AA), could attenuate PE-induced cardiac hypertrophy by regulating the modification of histone H3K9ac acetylation ( 4 ); however, the upstream signaling pathways were not determined.…”