Transforming growth factor β and its role in heart disease

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor beta (TGF beta) and its signaling pathways. TGF beta appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGF beta signaling involves its binding to TGF beta receptor type II (TGF beta RII), which recruits TGF beta receptor type I (TGF beta RI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGF beta levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGF beta signaling at different steps, affecting different components. Therapeutic targeting of TGF beta signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGF beta signaling pathway, for instance cardiac dysfunction and heart failure.