Combination of Amlexanox and Forskolin Attenuates Pathological Cardiac
Hypertrophy by Subduing Maladaptive Inflammatory Response
Abstract
Background and Purpose: The immune system is implicated in the
pathogenesis of pathological cardiac hypertrophy (PCH). However, there
is currently no therapeutic intervention to prevent PCH. Here, we aimed
at preventing pathological cardiac hypertrophy (PCH) during chronic
catecholamine stress via modulating adaptive inflammatory by targeting
adenylyl cyclases (ACs) and G protein-coupled receptor kinase 5 (GRK5)
in cardiomyocytes and immune cells. Experimental Approach: PCH was
induced in mice by chronic isoproterenol injections. In vitro,
peritoneal macrophages were challenged with lipopolysaccharide under
stress. Further experiments employed the therapeutic interventions
Amlexanox and Forskolin to inhibit GRK5 and activate ACs-cAMP,
respectively. Cardiac functions were assessed with echocardiography.
Inflammatory markers were assessed with ELISA and RT-qPCR (in vivo and
in vitro). GRK5 localizations in macrophages were assessed by
immunofluorescence, and alterations in protein expression were analyzed
with immunoblotting. Histological assessments were done with Masson,
H&E and IHC staining. Key Results: PCH mice had deteriorating cardiac
functions and morphological remodeling, accompanied by massive immune
cell infiltrations. Similarities were observed proinflammatory markers
upregulation, as were IL-10 found downregulated both in vivo and in
vitro. However, the combination of Amlexanox and Forskolin modulated
adaptive inflammatory responses and also maintained proper cardiac
morphology and function. The single therapies of neither Amlexanox nor
Forskolin were able to attain the aforementioned with much efficacy as
their combination therapy. Conclusion: The combination therapy of ALX
and FSK has the therapeutic potential of preventing the occurrence of
pathological cardiac hypertrophy during CCS by modulating adaptive
inflammatory responses while maintaining normal cardiac function.