Abstract 520: Peptide and SiRNA Modulation of HSP20 Influences Vasoreactivity

Abstract

Subarachnoid hemorrhages affect 30,000 people each year and accounts for between 1-7% of all strokes. Nearly 85% of the time that the hemorrhage occurs, it is due to a cerebral aneurysm that leads to delayed vasospasm and stroke. Traditional vasodilators cannot be used because they will cause systemic hypotension leaving an unmet clinical need. HSPB1 is a small heat shock related protein that modulates vasorelaxation, is downregulated in vasospastic vessels, and represents a potential therapeutic modality for the treatment of SAH-induced vasospasm. siRNA against HSPB1 that was encapsulated with a diblock copolymer to enhance uptake, or Rat aortic smooth muscle was tested with a HSPB1 phospho-peptide (HSPB1-p) +/- a polyplex delivery system (polyplexHSPB1). Intracellular calcium was measured concurrently with force using a Fluoroplex sysem. Knockdown of HSPB1 inhibited sodium nitroprusside (SNP)-induced relaxation of rat aorta. In conclusion, HSP20 modulates calcium independent relaxation of vascular smooth muscle and HSPB1-p may represent a novel therapeutic for vasospasm. Tissue treated with HSPB1-p or polyplex HSPB1-p had a dose dependent inhibition of contraction. The polyplex inhibited contraction at a lower dose of HSPB1-p than peptide alone with complete inhibition of contraction at 500 μM). Complete inhibition of contraction occurred without inhibition of increases in intracellular calcium concentrations ([Ca 2+ ] i ).