AdipoR1/APPL1 Potentiates the Protective Effects of Globular Adiponectin on Angiotensin II-Induced Cardiac Hypertrophy and Fibrosis in Neonatal Rat Atrial Myocytes and Fibroblasts

Abstract

Atrial hypertrophy and fibrosis are essential pathological features of atrial fibrillation. Recently, adiponectin has become a protein of interest due to its beneficial effects on cardiovascular diseases. However, the molecular mechanism of atrial structural remodeling and signaling pathways evoked by adiponectin remain unclear. In the present study, we investigated the cardioprotective effect of globular adiponectin (gAcrp) on angiotensin II-induced atrial hypertrophy and fibrosis in neonatal Sprague-Dawley rat. To further investigate the molecular mechanisms underlying the preventive effect of gAcrp, transfection of cells with siRNA was used to suppress the mRNA expression of adiponectin receptor 1 (AdipoR1) and its downstream adaptor protein APPL1. Non-silencing-Cy-3 labelled siRNA was used to determine transfection efficiency using fluorescence microscopy. The expression of atrial natriuretic peptide and procollagen type1 α-1, hypertrophy marker and fibrosis one, respectively, was detected by real-time PCR. Furthermore, the expression of adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K) and Akt was detected by western blotting. In addition, nuclear p65 translocation activity was analyzed by EMSA supershift assay. Our results showed that AdipoR1 and the adaptor protein APPL1 mediated the protective effects of gAcrp. In addition, the function of adiponectin and phosphorylation of AMPK were prominently diminished by inhibition of PI3K. Furthermore, nuclear factor-κB (NF-κB) transcription was diminished by the specific inhibition of AMPK. Taken together, AMPK pivotally interacts with NF-κB and PI3K, mediating the cardioprotective effect of adiponectin, and may serve as a therapeutic target for preventing atrial hypertrophy and fibrosis. Our present study suggests that gAcrp could ameliorate AngII-induced cardiac hypertrophy and fibrosis in rat atrial cells, which is mediated by the activation of AMPK signaling pathways. APPL1 and AdipoR1 are the key factors involved in the downstream of gAcrp approach.

Correlation between adiponectin and hemorrhagic shock in mice

“…Many studies have documented the involvement of ADPN in the termination of inflammation by at least two mechanisms: the first is through the inhibition of the function of mature macrophages and the second is the growth of granulocyte-monocyte progenitor cell lines. The former mechanism plays an important role in acute inflammation while the latter mechanism plays a major role in chronic inflammation in order to avoid excessive immune response (Antonopoulos et al, 2014;Cao et al, 2014;Li et al, 2015). Additionally, the findings in our present study demonstrate that the serum level of ADPN in mice increase in the early period of HS, which is in accordance with the varying trend of IL-37 in the same HS model.…”

C1q/tumor necrosis factor-related protein-6 attenuates post-infarct cardiac fibrosis by targeting RhoA/MRTF-A pathway and inhibiting myofibroblast differentiation

“…Adiponectin protects against cardiac dysfunction induced by MI or angiotensin II via suppressing cardiac hypertrophy and interstitial fibrosis [3,11,32]. Globular adiponectin attenuates myocardial ischemia/reperfusion injury [13].…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…Multiple studies have reported exaggerated pathological cardiac hypertrophy in adiponectin knockout mice under experiment models of pressure overload (61-63) with adiponectin replenishment resulting in reduced pathologic hypertrophy (62). Experiments in isolated neonatal rat ventricular myocytes treated with angiotensin II to induce hypertrophy illustrated that the primary anti-hypertrophic mechanism of adiponectin occurred through AdipoR1-APPL1-AMPK activation resulting in suppression of nuclear factor kappa-B-induced hypertrophic growth signaling (64)(65)(66). These studies suggest that adiponectin can protect against cardiac hypertrophy and lack of adiponectin can lead to development of more severe pathological hypertrophy.…”