Abstract 3617: Secretory Leucocyte Protease Inhibitor and Matricellular Protein Modulation of Post Reperfused Myocardial Infarction Healing, Fibrosis and Remodeling in Rat Model: Effect of Candesartan and Omapatrilat
Mice deficient in secretory-leucocyte-protease-inhibitor (SLPI) have impaired healing of skin wounds and SLPI may improve post infarct healing and remodeling. Studies in mice suggest matricellular proteins such as secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) may also improve remodeling. Angiotensin II is known to regulate extracellular matrix (ECM) and drive left ventricular (LV) remodeling. We hypothesized that the angiotensin II type 1 receptor blocker candesartan (CN) and vasopeptidase inhibitor omapatrilat (OMA) can modulate SLPI, SPARC and OPN and improve healing and ECM remodeling after reperfused myocardial infarction (RMI). We measured LV function and remodeling during healing (echocardiography at baseline, day-2 and day-22) in Sprague-Dawley rats with RMI (1-h coronary occlusion; reperfusion) or sham, and regional expression of SLPI, SPARC, OPN, inflammatory cytokines, matrix metalloproteinase (MMPs) and infarct scar parameters at 3 weeks. We randomized rats with RMI to oral placebo, CN (30 mg/kg) or OMA (10 mg/kg) between 24-h and 3 weeks. The doses of CN and OMA inhibited pressor responses to angiotensin II and I, respectively. Compared to sham, placebo-RMI induced moderate-sized infarcts and LV remodeling and dysfunction. Compared to non-infarct zones, placebo-RMI induced robust (P<0.001) increase in mRNA and protein expression (RT-PCR/Western-blot) of SLPI, SPARC and OPN in ischemic zones. Additionally, placebo-RMI increased MMP-9 and MMP-2, inducible-nitric-oxide-synthase, pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α, transforming growth factor-β1, Smad-2, myeloperoxidase, scar collagens and cross-linking and decreased anti-inflammatory cytokine IL-10. Compared to placebo, CN and OMA reversed these molecular and biochemical changes, promoted healing and limited fibrosis, remodeling and dysfunction after RMI. Together, the findings suggest that CN- and OMA-induced mitigation of increases in SLPI, SPARC and OPN expression and concomitant decreases in inflammatory cytokines, MMPs, oxidants, scar collagens and cross-linking contribute in healing and limiting fibrosis, LV remodeling and dysfunction during healing after RMI in the rat model.