Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

1.4.2 STATs as Mediators of Myocardial Cell Death
STAT1 activity is upregulated in cardiac myocytes following simulated I/R and exacerbates
cardiac damage through induction of pro-apoptotic STAT1 effectors, such as caspase1, Fas
and FasL (Stephanou et al., 2000). Support for the role of STAT1 as a pro-apoptotic factor in
the myocardium comes from studies which show that inhibition of STAT1 activity during I/R
results in significant cardioprotection. For example, both infusion and oral administration of
the green tea polyphenol extract epigallocatechin-3-gallate reduced infarct size and caspase
activity following I/R in a STAT1 dependent manner (Townsend et al., 2004). A pro-
apoptotic role has also been ascribed to STAT1 in neuronal ischaemia, STAT1 deficient mice
show reduced neurological damage following ischaemia and this was associated with reduced
caspase 3 activity and reduced neuronal cell death (Takagi et al., 2002). Many of the
propapototic effects of STAT1 are attributable to the C-terminal domain, with
phosphorylation at serine 727 being indispensable for I/R induced apoptosis and Fas/FasL
expression (Stephanou et al., 2002). Interestingly, S727 phosphorylation of STAT1 is
necessary for PKC induced apoptosis following DNA damage (DeVries et al., 2004). The
proapoptotic effects of STAT1 can be blocked by p38 MAPK inhibition, suggesting cross-
talk between the JAK-STAT pathway and the MAP kinase pathway during I/R injury
(Stephanou et al., 2001). There is far less data concerning the role of STAT3 in I/R injury in
the myocardium but some studies have suggested that STAT3 may have cytoprotective roles
in the heart. STAT3 overexpression protected mice from doxorubicin induced
cardiomyopathy and transfection of STAT3 into cardiac myocytes abrogated the proapoptotic
effects of STAT1 following I/R injury (Negoro et al., 2000, Stephanou et al., 2004).
1.4.3 JAK/STAT Pathway in Ischaemic Preconditioning
Preconditioning (PC) refers to the administration of transient sublethal episodes of ischaemia
before a prolonged I/R injury, which renders the heart less susceptible to the deleterious
effects of I/R mediated damage. PC can reduce infarct size by up to 80%, providing a very
efficacious adjunctive therapy where reperfusion injury is unavoidable (Xuan et al., 2003).
PC can be divided into two separate phases, an early phase which occurs immediately after
reperfusion and lasts for up to 2 hr and a late phase which is sustained for up to 72 hr. Several
studies from Roberto Bolli’s group and others have recently uncovered the obligatory role of
the JAK/STAT pathway in mediating the cardioprotective effects of late PC through iNOS
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