LCZ696 attenuated doxorubicin-induced heart injury through the
TLR2-MyD88 pathway
Abstract
Background and Purpose: The profibrotic and proinflammatory effects
induced by doxorubicin (DOX) are key processes in the development of
serious heart damage. The lack of effective drugs and the unclear
mechanisms of their side effects limit the clinical treatment of
DOX-induced cardiac injury. This study aimed to explore the protective
role of LCZ696 and the potential mechanism of Toll-like receptor 2
(TLR2) in doxorubicin-induced cardiac failure. Experimental Approach:
DOX (5 mg/kg/week, 3 times) was used to establish a chronic
cardiomyopathy mouse model. Heart function tests, pathology examinations
and molecular biology analyses were used to explore the effects of
LCZ696 and TLR2 deficiency. H9C2 cells were used to verify the
protective role and mechanism of LCZ696 in vitro. Key Results: The EF%
declined, and the LVIDd, pro-fibrosis marker levels and NF-κB
pathway-related inflammatory response increased in the chronic
cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2
deficiency reversed this heart damage in vivo. In H9C2 cells,
pretreatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced
high expression of profibrotic and proinflammatory markers. Moreover,
DOX notably increased the TLR2-MyD88 interaction in H9C2 cells, which
was inhibited by LCZ696 pretreatment. Conclusion and Implications:
LCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and
inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696
may be a potential effective drug to treat DOX-induced heart failure.