Pivotal Role of TGF-ß/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players.

ABSTRACT

Unintended cardiac fibroblast proliferation in many pathophysiological heart conditions, known as cardiac fibrosis, results in pooling of extracellular matrix (ECM) proteins in the heart muscle. Transforming growth factor ß (TGF-ß) as a pivotal cytokine/growth factor stimulates fibroblasts and hastens ECM production in injured tissues. The TGF-ß receptor is a heterodimeric receptor complex on the plasma membrane, made up from TGF-ß type I, as well as type II receptors, giving rise to Smad2 and Smad3 transcription factors phosphorylation upon canonical signaling. Phosphorylated Smad2, Smad3, and cytoplasmic Smad4 intercommunicate to transfer the signal to the nucleus, culminating in provoked gene transcription. Additionally, TGF-ß receptor complex activation starts up non-canonical signaling that lead to the mitogen-stimulated protein kinase cascade activation, inducing p38, JNK1/2 (c-Jun NH2-terminal kinase 1/2), and ERK1/2 (extracellular signal-regulated kinase 1/2) signaling. TGF-ß not only activates fibroblasts and stimulates them to differentiate into myofibroblasts, which produce ECM proteins, but also promotes fibroblast proliferation. Non-coding RNAs (ncRNAs) are important regulators of numerous pathways along with cellular procedures. MicroRNAs and circular long ncRNAs, combined with long ncRNAs, are capable of affecting TGF-ß/Smad signaling, leading to cardiac fibrosis. More comprehensive knowledge based on these processes may bring about new diagnostic and therapeutic approaches for different cardiac disorders.