Grant: Travel Awards - Institute Community Support

Cardiac remodeling is the process by which cardiac structure and/or function change in response to pathophysiological derangements such as disease states, chronic arrhythmic conditions or altered hormone balance. Cardiac remodeling promotes mechanical dysfunction of the heart and arrhythmia generation. The traditional view of the signal transduction pathways leading to the gene-expression changes that cause remodeling has been that molecules interact with cell membrane receptors and modulate the production and/or breakdown of intracellular second messengers, which diffuse into the nucleus and modify gene-transcription. Recent work has suggested that ligands may also act via receptors on intracellular organelles, and not just exclusively via surface-membrane receptors: so-called "intracrine signaling". There is evidence that AT1R (Angiotensin Type 1 receptor) and AT2R (Angiotensin Type 1 receptor) localized to the nuclear envelope may play significant roles in cardiac remodeling. Nuclear receptors with the ability to regulate cardiac gene-expression have been demonstrated for Ang-II, endothelin, beta-adrenergic agonists and opioid ligands. How do peptide ligands get into the cell to act on intracellular receptors? Intracrine ligands may be synthesized de novo intracellularly (e.g. FB growth factor, opioids, Ang-II), may be transported actively (noradrenaline) or via passive diffusion (leukotrienes) from the extracellular space, or may move into the cell within internalized endosomes. The nucleus contains all the key components of G-protein receptor-coupled signaling pathways, which if activated would be strategically located to regulate gene-transcription pathways. Relevant consequences could be the development of compounds selected for their ability to concentrate (or not) intracellularly, as well as novel drug-delivery approaches to the development of agents that act principally within the cell.