During
myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse
ventricular remodeling. We investigated whether
dapagliflozin, a
sodium-glucose cotransporter 2 (
SGLT2) inhibitor, attenuates cardiac
fibrosis via regulating macrophage phenotype by a reactive
oxygen and
nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary
ligation and then randomized to either saline,
dapagliflozin (a specific
SGLT2 inhibitor),
phlorizin (a nonspecific SGLT1/2 inhibitor),
dapagliflozin +
S3I-201 (a STAT3 inhibitor), or
phlorizin +
S3I-201 for 4 weeks. There were similar
infarct sizes among the infarcted groups at the acute and chronic stages of
infarction. At day 3 after
infarction, post-
infarction was associated with increased levels of
superoxide and
nitrotyrosine, which can be inhibited by administering either
dapagliflozin or
phlorizin.
SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial
IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after
infarction,
SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac
fibrosis. Although
phlorizin decreased myofibroblast infiltration, the effect of
dapagliflozin on attenuated myofibroblast infiltration was significantly higher than
phlorizin. The effects of
SGLT2 inhibitors on cardiac
fibrosis were nullified by adding
S3I-201. Furthermore, the effects of
dapagliflozin on STAT3 activity and myocardial
IL-10 levels can be reversed by 3-morpholinosydnonimine, a
peroxynitrite generator. Taken together, these observations provide a novel mechanism of
SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective
SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling.