Dual Activity Of Ginsenoside Rb1 In Hypertrophic Cardiomyocytes And Activated Macrophages: Implications For The Therapeutic Intervention Of Cardiac Hypertrophy

Purpose: Owing to the important mechanistic implications in the pathogenesis of cardiac hypertrophy and heart failure, inflammation has been proposed as a druggable target for the treatment of cardiac hypertrophy and heart failure. Ginseng is a widely used medicinal herb for the treatment of cardiovascular disorders. As one of the major chemical components of ginseng, ginsenoside Rb1 (Rb1) contributes to the cardiovascular effects of ginseng. Meanwhile, anti-inflammatory activity of Rb1 has also been documented. The current work aims to further delineate the pharmacological implications of Rb1 in the treatment of cardiac hypertrophy.Methods: Angiotensin II (Ang II) infusion mouse model was adopted to investigate the effects of Rb1 on cardiac hypertrophic remodeling and associated inflammation in vivo. Furthermore, the mechanisms of actions of Rb1 in modulating the hypertrophic and inflammatory responses were investigated in cardiomyocytes and macrophages, respectively.Results: Rb1 mitigates Ang II-induced cardiac hypertrophy, cardiac inflammation and systemic inflammation in vivo. In cardiomyocytes, Rb1 directly counteracts the prohypertrophic effects of Ang II and phenylephrine and maintains the mitochondrial function. In lipopolysaccharide (LPS)-stimulated macrophages, Rb1 decreases the phosphorylation of mitogen-activated protein kinases (MAPKs) and mitogen-activated protein kinase kinase 1/2 (MEK1/2) and reduces the production of inflammation mediators such as interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF). Rb1 also suppresses the expression of prohypertrophic microRNA-155 (miR-155) in LPS- or Ang II-stimulated macrophages. Furthermore, in activated macrophages, miR-155 is in part accountable for the suppressive effect of Rb1 on the production of IL-6, an inflammation mediator with pro-hypertrophic functions in the heart.Conclusion: The work here provides novel experimental evidence supporting the notion that Rb1 protects against cardiac hypertrophy in part through suppressing the inflammatory mechanisms that promotes the pathological remodeling of the heart.