Knowledge Bank

Heart failure affects over 6 million Americans with an increasing need to prevent the progression of this disease. The TGF-β pathway is a signal transduction pathway involved in cell proliferation, apoptosis, fibrosis, and more, both in homeostasis and in disease states. β2 spectrin is a cytoskeletal protein involved in maintaining cellular structural integrity and cardiac excitability as well as functions as a key adaptor protein for SMAD3 and SMAD4. While there are data describing complete knockdown of β2 spectrin and its effects in the TGF-β/SMAD pathway from an embryological/developmental perspective, there is a knowledge gap regarding the function of β2 spectrin in the adult heart. Using a novel transgenic model, we sought to define the importance of β2 spectrin in the TGF-β/SMAD pathway in the adult heart. I hypothesized that β2 spectrin is a key adaptor protein in the TGF-β/SMAD pathway required for downstream transcription of fibrotic genes, and chronic TGF-β stimulation leads to increased intracellular calcium and thus calpain activity which cleaves β2 spectrin leading to HF. Our preliminary data using immunoblotting analysis demonstrated that there were significantly decreased expression of Collagen 1, the most significant fibrotic protein, as well as TGF-β1, and TGF-β2, suggesting that the canonical TGF-β is greatly affected. Inversely, it was seen that there are no significant changes in SMAD2, SMAD3, SMAD4 expression, but increased expression of SMAD7. Together, these data indicate that β2 spectrin does play a role in the TGF-β/SMAD pathway, but there is more work that must be done in order to elucidate the complete mechanism. Further in vitro studies in HL-1 cells and cardiac fibroblasts as well as the use of a HF transverse aortic constriction (TAC) mouse model would be ideal future studies to mechanistically determine if calpain inhibition could be used to minimize and reduce fibrosis which would lead to improved outcomes in heart failure.