Address correspondence to:
Prof. Hong Sun (MD, Ph.D.). Department of Physiology, Xuzhou Medical
University, 209 Tongshan Road,Xuzhou,221004, Jiangsu, China. Phone:
+86-516-83262618, Fax: +86-516-83262858. Email:
sunh@xzhmu.edu.cn.
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.
Keywords: Chronic
Catecholamine Stress, Inflammation, Pathological Cardiac Hypertrophy,
Amlexanox, Forskolin