Abstract
Agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) can activate 5′ AMP-activated protein kinase alpha (AMPKα) and exert cardioprotective effects. A previous study has demonstrated that rosmarinic acid (RA) can activate PPAR-γ, but its effect on cardiac remodeling remains largely unknown. Our study aimed to investigate the effect of RA on cardiac remodeling and to clarify the underlying mechanism. Mice were subjected to aortic banding to generate pressure overload induced cardiac remodeling and then were orally administered RA (100 mg/kg/day) for 7 weeks beginning 1 week after surgery. The morphological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. To ascertain whether the beneficial effect of RA on cardiac fibrosis was mediated by AMPKα, AMPKα2 knockout mice were used. Neonatal rat cardiomyocytes and fibroblasts were separated and cultured to validate the protective effect of RA in vitro. RA-treated mice exhibited a similar hypertrophic response as mice without RA treatment, but had an attenuated fibrotic response and improved cardiac function after pressure overload. Activated AMPKα was essential for the anti-fibrotic effect of RA via inhibiting the phosphorylation and nuclear translocation of Smad3 in vivo and in vitro, and AMPKα deficiency abolished RA-mediated protective effects. Small interfering RNA against Ppar-γ (siPpar-γ) and GW9662, a specific antagonist of PPAR-γ, abolished RA-mediated AMPKα phosphorylation and alleviation of fibrotic response in vitro. RA attenuated cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling and PPAR-γ was required for the activation of AMPKα. RA might be a promising therapeutic agent against cardiac fibrosis.
Highlights
Cardiac remodeling, characterized as cardiomyocyte hypertrophy and interstitial fibrosis, is a leading risk factor for heart failure, arrhythmia, and sudden death[1,2]
Enhanced phosphorylation and nuclear translocation of Smad[3] in fibroblasts was largely responsible for the aggravating fibrosis phenotype following myocardial infarction[8]. These results indicated that inhibition of Smad[3] might be beneficial for alleviating cardiac fibrosis and that unearthing a negative regulator of Smad[3] could be of paramount clinical importance. 5′ AMP-activated protein kinase (AMPK) has been recognized as a key regulator of energy metabolism in the heart; current available studies implied that AMPK extended well beyond its energy-regulating function and played a crucial role in regulating cardiac fibrosis[11,12]
We examined the potential effect of rosmarinic acid (RA) on cardiac hypertrophy and observed similar hypertrophic responses in mice with or without RA treatment, as revealed by the similar increases in heart weight (HW)/body weight (BW), HW/tibia length (TL), and interventricular septal thickness at systole or diastole (IVSs or IVSd) (Figs. 1e-h)
Summary
Cardiac remodeling, characterized as cardiomyocyte hypertrophy and interstitial fibrosis, is a leading risk factor for heart failure, arrhythmia, and sudden death[1,2]. Zhang et al Cell Death and Disease (2018)9:102 orchestrating cardiac fibrosis; effective strategies that targeting CFs may help to develop efficacious interventions against fibrosis, mitigate cardiac remodeling, and postpone the development of heart failure[7]. Enhanced phosphorylation and nuclear translocation of Smad[3] in fibroblasts was largely responsible for the aggravating fibrosis phenotype following myocardial infarction[8]. These results indicated that inhibition of Smad[3] might be beneficial for alleviating cardiac fibrosis and that unearthing a negative regulator of Smad[3] could be of paramount clinical importance. AMPK deficiency exacerbated transverse aortic constriction-induced cardiac fibrosis, whereas the activation of AMPK attenuated cardiac fibrosis[11,13]
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