Abstract
Many studies have focused on identifying therapeutic targets of myocardial hypertrophy for the treatment of correlative cardiac events. Wogonin is a natural flavonoid compound that displays a potent anti-hypertrophic effect. Knowledge of its pharmacological mechanisms might reveal an effective way to search for therapeutic targets. Myocardial hypertrophy was replicated by the subcutaneous implantation of an isoprenaline mini-pump in mice or isoprenaline treatment of H9C2 cells. Pathologic changes in cardiac structure were assessed by echocardiographic and histological examinations. The signaling transduction in hypertrophy-promoting pathways and the genes involved were detected by western blot and RT-qPCR. Wogonin significantly attenuated isoprenaline-induced myocardial hypertrophy in vivo and in vitro by suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) hypertrophy-promoting pathway. Wogonin promoted the ubiquitination and degradation of PI3K catalytic subunit alpha (Pik3ca), the catalytic subunit of PI3K, which was upregulated by isoprenaline treatment. Wogonin also increased the expression of neural precursor cells expressing developmentally down-regulated gene 4-like (Nedd4l), the ubiquitin E3 ligase of Pik3ca. Therefore, wogonin targets Nedd4l to induce the degradation of Pik3ca, which reverses the over-activation of the PI3K/Akt pathway and consequently relieves the isoprenaline-induced myocardial hypertrophy.
Highlights
Myocardial hypertrophy is characterized by thickening of the ventricle wall in the heart, an adaptive response to, for example, mechanical and neurohumoral stimulations (Hill and Olson, 2008; Maillet et al, 2013)
The detailed anatomical changes in the heart were detected by echocardiography and reflected via hypertrophic indexes including heart weight (HW), HW/body weight (BW), interventricular septum diameter (IVSd), left ventricular posterior wall diameter (LVPWd), left ventricular (LV) Mass, left ventricular end-diastolic diameter (LVIDd), and left ventricular end-systolic diameter (LVIDs)
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are two well-known natriuretic peptides secreted by cardiac muscle cells when hypertrophy occurs (Vasan, 2006)
Summary
Myocardial hypertrophy is characterized by thickening of the ventricle wall in the heart, an adaptive response to, for example, mechanical and neurohumoral stimulations (Hill and Olson, 2008; Maillet et al, 2013). Β-adrenoceptors, locating on the membranes of the three major cardiac cell types (cardiomyocytes, fibroblasts, and endothelial cells), belong to the G protein-coupled receptor superfamily (Kawano et al, 2009). Their stimulation activates downstream signaling pathways that regulate different intracellular, sarcolemmal, and myofibrillar substrates (Feldman et al, 2005; Siryk-Bathgate et al, 2013). The Gαi subunit activates the PI3K/Akt and mitogen-activated protein kinase (MAPK) signaling pathways both promoting myocardial hypertrophy (Esposito et al, 2002; Lohse et al, 2003; Feldman et al, 2005; Heineke and Molkentin, 2006; Go et al, 2014). Β-adrenoceptor signaling pathway should likely contain some potential targets for myocardial hypertrophy therapy
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