Conclusions
In summary, we demonstrated in vitro that the combination of ALX and FSK
could attenuate LPS-induced hyperactive proinflammatory from
PMɸ during CCS. We then induced PCH in mice and
translated the therapies of ALX and FSK in vivo to attenuated the biased
proinflammatory immune responses that exacerbate myocyte necrosis and
massive collagen deposit during CCS. We investigated the underlying
mechanisms of the combination therapy and demonstrated that besides ALX
preventing the occurrence of abnormal myocytes hypertrophy, it
complemented the efforts of FSK – ACs – cAMP-mediated immunoregulation
by abolishing GRK5-mediated induction of inflammatory responses
(Fig.10). However, singly, neither FSK nor ALX has the therapeutic
potential of attenuating PCH by subduing maladaptive inflammatory
response while maintaining proper cardiac function during CCS. Also,
although ACs and GRKs exhibit a negative correlation in healthy and
failing cardiac and immune systems, their mode of actions and pathways
are independent of each other.