Combination of ALX and FSK preserved cardiac function during CCS
Cardiac function assessed at the end of animal models using
echocardiogram demonstrated cardiac function deteriorated during CCS.
Compared with the PCH mice and ALX single therapy, FSK single therapy
improved cardiac function to some extent, but it was accompanied by
arrhythmias. However, the combination of ALX and FSK preserved cardiac
function most effectively compared to the single therapy groups (Fig.
5a-5c, Supplementary Fig. S4 and Table S2). There was no statistical
significance upon comparing cardiac functions of mice from the
PCH-preventive combine therapy group with Ctrl and Vhl mice. The Vhl
mice group is representing the Ctrl mice group as well in results
illustrations due to similarity in their data.
A further critical assessment of molecular alterations in the apical
myocardium across all groups demonstrated that overall, the combination
of ALX and FSK preserved cardiac function during CCS by normalizing
expressions of the proteins and TFs that play critical roles in cardiac
function and immune response modulation.
Among the therapeutic groups, β1AR depletion was
minimized by the combined therapy, while β2AR expression
was somewhat maintained across all the groups. Compared to the Vhl and
PCH mice, the expression of AC5 and AC7 were mostly normalized by the
combined therapy, although FSK single treatment did better against ALX
single treatment. AC6 was still observed increasing its expression in
stress intensity-dependent manner across groups. Even though ALX alone
inhibited GRK5 activities, it had no inhibitory effect on GRK2; neither
did only FSK. FSK single treatment also minimized the upregulation of
GRK5 but not as effective as ALX single treatment and their combined
treatment. The combination therapy again was the best in regulating ANP
and BNP expressions during CCS (Fig. 6a). The normalization of ACs by
the combination therapy was translated into normalized cAMP
concentrations as well (Fig. 6b).
Intriguingly, despite the inhibition GRK5 by the ALX single treatment,
ERK1/2 was maladaptively engaged, and the TFs; GATA4, NFAT, MEF2, and
NF-κB were upregulated just like in PCH mice. FSK single therapy did
better at modulating the overexpression of these cardiac and
inflammatory TFs, but the ALX and FSK combination therapy did best
(Fig.7)