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Combination of Amlexanox and Forskolin Attenuates Pathological Cardiac Hypertrophy by Subduing Maladaptive Inflammatory Response
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  • Gabriel Adzika,
  • Hongjian Hou,
  • Adebayo Adekunle,
  • Ruqayya Rizvi,
  • Tongtong Ma,
  • Seyram Adzraku,
  • Li Kexue,
  • Qi-Ming Deng,
  • Richard Mprah,
  • Marie Louise Ndzie Noah,
  • Jeremiah Machuki,
  • Stephane Koda,
  • Xianluo Ma,
  • Hong Sun
Gabriel Adzika
Xuzhou Medical University
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Hongjian Hou
Xuzhou Medical University
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Adebayo Adekunle
Xuzhou Medical University
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Ruqayya Rizvi
Xuzhou Medical University
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Tongtong Ma
Xuzhou Medical University
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Seyram Adzraku
The Affiliated Hospital of Xuzhou Medical University
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Li Kexue
Xuzhou Medical University
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Qi-Ming Deng
Shandong University Affiliated Hospital
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Richard Mprah
Xuzhou Medical University
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Marie Louise Ndzie Noah
Xuzhou Medical University
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Jeremiah Machuki
Xuzhou Medical University
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Stephane Koda
Xuzhou Medical University
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Xianluo Ma
People's Hospital of Jiawang District
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Hong Sun
Xuzhou Medical University
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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.