Spermidine/spermine-N¹-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice

Abstract

Expression of spermine/spermidine-N1-acetyltransferase (SSAT), the rate-limiting enzyme of polyamine backconversion cascade, increases after ischemia-reperfusion injuries (IRI). We hypothesized that SSAT plays an important role in the mediation of IRI. To test our hypothesis, wild-type (SSAT-wt) and SSAT-deficient (SSAT-ko) mice were subjected to liver or kidney IRI by ligation of hepatic or renal arteries. The liver and kidney content of putrescine (Put), a downstream by-product of SSAT activity, increased in SSAT-wt animals but not in SSAT-ko animals after IRI, indicating that polyamine backconversion is not functional in SSAT-deficient mice. When subjected to hepatic IRI, SSAT-ko mice were significantly protected against liver damage compared with SSAT-wt mice. Similarly, SSAT-ko animals subjected to renal IRI showed significantly greater protection against damage to kidney tubules than SSAT-wt mice. These studies indicate that SSAT-deficient animals are protected against IRI and suggest that SSAT is an important mediator of the tissue damage in IRI.

Hepatocyte-specific ablation of spermine/spermidine-N1-acetyltransferase gene reduces the severity of CCl4-induced acute liver injury

“…The maladaptive role of SSAT in the induction of cellular damage and tissue injury is supported by in vitro and in vivo observations (1,4,5,11,25,32,(35)(36)(37). In vitro studies indicate that expression of SSAT in cultured cells leads to induction of oxidative stress, DNA damage, cell cycle arrest, and onset of the intrinsic/ caspase-dependent apoptosis (7,36).…”

“…Previous studies comparing the extent of organ injury and dysfunction in WT and SSAT-ko mice indicate that SSAT deficiency reduces the severity of a variety of injuries (35,37). On the basis of the aforementioned observations, we set out to test the hypothesis that enhanced expression of SSAT by hepatocytes contributes to their damage and liver dysfunction in CCl 4 -induced injury.…”

“…Increased expression of SSAT, and the attendant enhancement of polyamine catabolism contribute to cell damage and organ dysfunction in a variety of injuries (4,35,37,39). To determine the role of SSAT in CCl 4 -induced liver injury, WT and Hep-SSAT-Cko mice were given a single intraperitoneal injection of CCl 4 .…”

“…1). The expression and activity of SSAT increases in organs (e.g., liver, kidney, and brain) subjected to ischemia-reperfusion and septic and traumatic injuries (4,35,37,39). The ablation of the SSAT gene reduces the severity of renal and hepatic ischemia-reperfusion and endotoxin-induced renal injuries (35,37).…”

“…The ablation of the SSAT gene reduces the severity of renal and hepatic ischemia-reperfusion and endotoxin-induced renal injuries (35,37). Transgenic animals that express high levels of SSAT develop several pathologies, including skin lesions and pancreatitis (1,24,25).…”