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.