Overexpression of Human Copper/Zinc Superoxide Dismutase (SOD1) Suppresses Ischemia–Reperfusion Injury and Subsequent Development of Graft Coronary Artery Disease in Murine Cardiac Grafts

Abstract

Background-Ischemia-reperfusion injury is an important risk factor for graft coronary artery disease (GCAD). We hypothesized that overexpression of SOD1 in donor hearts would suppress ischemia-reperfusion injury and thereby reduce GCAD. Methods and Results-In one series, donor hearts of C57BL/6 (H-2 b ) transgenic mice overexpressing human SOD1 or C57BL/6 wild-type mice were heterotopically transplanted into C57BL/6 recipients and procured after 4 hours of reperfusion (nϭ6 each). Superoxide, TNF-␣, and MCP-1/CCL2 production were significantly reduced in the SOD1 transgenic donor heart recipients, and graft injury determined by serum CPK-MB levels was significantly decreased. Cardiomyocyte apoptosis and caspase-3 and caspase-9 activities were significantly decreased in these recipients; caspase-8 activity was unchanged. Fas ligand but not Fas expression was also reduced. In a second series, transgenic and wild-type hearts were transplanted into C-H-2 bm12 KhEg (H-2 bm12 ) recipients, and then procured on day 56 (nϭ7 each). Cardiac graft beating was significantly better in the SOD1 transgenic donor heart recipients on days 28, 42, and 56 (but not day 14). Significant reduction in luminal narrowing, the intima/media ratio, and the percentage of diseased vessels was seen in the SOD1 transgenic donor heart recipients, and MCP-1/CCL2, ICAM-1, and VCAM-1 production were significantly reduced. Conclusions-Overexpression of SOD1 attenuates both apoptosis and the inflammatory response during ischemiareperfusion injury and therefore mitigates against the subsequent development of GCAD.

Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion

“…46 Intriguingly, ischemia-reperfusion injury is also a well-known alloantigen-independent risk factor for acute allograft rejection and subsequent cardiac allograft vasculopathy. 47,48 Although not directly tested in this study, other IL-17-producing cells likely participate during the pathogenesis, because the acute allograft rejection noted in ␥␦ T cell-deficient mice was not as severe as WT controls. These findings support potential development of immunosuppressive agents directed at ␥␦ T cells.…”

Baicalin Attenuates Acute Myocardial Infarction of Rats <i>via</i> Mediating the Mitogen-Activated Protein Kinase Pathway

“…Caspase-3, the major form of caspase, is served as an "apoptotic executor" that cleaves substrates, such as ploy(AdP-ribose) polymerase, finally leading to DNA fragmentation and cell loss. 28) A remarkable elevation of caspase-3 was previously found in isoproterenol-induced acute myocardial infarction in Wistar rats. 24) our current study reported the consistent alteration of caspase-3 in infarcted hearts and meanwhile baicalin treatment obviously decreased caspase-3 expressions as well as its activity in the rats undergoing acute myocardial infarction.…”

MicroRNA-1 aggravates cardiac oxidative stress by post-transcriptional modification of the antioxidant network

“…Excess H 2 O 2 is normally reduced to water by catalase or glutathione peroxidase, preventing the production of hydroxyl radicals. It has been shown that SOD1 plays an important role in suppressing superoxide generation, apoptosis, and the inflammatory response in oxidative stress-related cardiac diseases (Mital et al 2011;Tanaka et al 2004;Chen et al 2000;Land et al 1994).…”