Understanding the role of chondroitin sulfate proteoglycan 4-sulfation in the heart following myocardial infarction

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PROJECT SUMMARY Sudden cardiac failure from cardiac arrhythmias is a leading cause of death for patients who have suffered a myocardial infarction (MI). Heterogeneity in sympathetic neurotransmission to damaged areas of the heart is thought to generate these arrhythmias. Following an early period of denervation after MI, the damaged cardiac tissue, or cardiac scar, has the capacity to stimulate nerve reinnervation due to high amounts of secreted Nerve Growth Factor (NGF) which activates tropomyosin receptor kinase A (TrkA). Despite this, nerves do not grow back into the scar due to the presence of chondroitin sulfate proteoglycans (CSPGs), resulting in a patchwork of innervation and denervation throughout the heart. The resulting denervated tissue is unable to respond to sympathetic neurotransmission leading to a heterogeneous response that generates cardiac arrhythmias. Previous work in our lab demonstrated that blocking CSPG signaling in sympathetic nerves restores sympathetic innervation of the cardiac scar and reduces arrhythmia susceptibility after MI. Therapeutic interventions to block CSPG signaling and restore sympathetic innervation of the cardiac scar would be a viable strategy to reduce post-MI arrhythmias and risk of sudden cardiac death but therapeutic design is limited by our understanding of CSPG signaling. CSPGs are a diverse family of molecules composed of different core proteins modified by glycosaminoglycans (GAG) side chains that can be further modified by sulfation. Evidence from research in the central nervous system (CNS) suggests that inhibition of axon outgrowth occurs primarily via 4S-CSPGs following nerve injury. Despite the critical role of CSPGs in preventing reinnervation of the cardiac scar it is unknown whether 4S- CSPGs specifically inhibit sympathetic axon outgrowth. This study will provide a mechanistic understanding of how CSPG sulfation in the cardiac scar affects sympathetic denervation in our mouse model of MI using the enzyme Arasulfatase B which selectively degrades 4S-CSPGs. Furthermore, CSPG-sulfation-induced signaling studies focusing downstream of TrkA signaling networks will elucidate the molecular mechanism behind sympathetic axon outgrowth inhibition. To understand signaling pathways a FRET based imaging platform will be used to examine multiple signaling pathways in parallel. These results will identify novel therapeutic targets to restore sympathetic axon outgrowth in the presence of CSPGs