Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction

While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague-Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible-nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-alpha, transforming growth factor (TGF)-beta(1) and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study.