Gallic Acid Ameliorates Angiotensin II-Induced Atrial Fibrillation by Inhibiting Immunoproteasome- Mediated PTEN Degradation in Mice

Abstract

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and is a major cause of stroke and heart failure. We and others have found that gallic acid (GA) plays a beneficial role in cardiac hypertrophic remodeling and hypertension. However, the effect of GA on angiotensin II (Ang II)-induced AF and atrial remodeling as well as the underlying mechanisms remain unknown. AF was induced in mice by Ang II infusion (2000 ng/kg/min) for 3 weeks. Blood pressure was measured using the tail-cuff method. Atrial volume was evaluated by echocardiography. Atrial remodeling was studied using hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining. Atrial oxidative stress was assessed by dihydroethidium staining. The gene expression of fibrotic and inflammatory markers and protein levels of signaling mediators were measured by quantitative real-time PCR and western blot analysis. In mice, GA administration significantly attenuated Ang II-induced elevation of blood pressure, AF incidence and duration, atrial dilation, fibrosis, inflammation, and oxidative stress compared with the vehicle control. Furthermore, GA downregulated Ang II-induced activity and expression of immunoproteasome subunits (β2i and β5i), which reduced PTEN degradation and led to the inactivation of AKT1 and downstream signaling mediators. Importantly, blocking PTEN activity by VO-Ohpic markedly reversed the GA-mediated protective effects on Ang II-induced AF and atrial remodeling. Therefore, our results provide novel evidence that GA exerts a cardioprotective role by inhibiting immunoproteasome activity, which attenuates PTEN degradation and activation of downstream signaling, and may represent a promising candidate for treating hypertensive AF.

Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms

“…To explain how Ang II induces lymphatic vessel permeability by reducing MKP5 and VE-cadherin protein levels and activating p38 MAPK, we measured proteasome activity and examined the levels of proteasome catalytic subunits in vivo and in vitro. Consistent with previous reports in CMs, endothelial cells, and other cell types from Ang II-infused mice [26,29,51], Ang II treatment also significantly upregulated the expression of the immunoproteasome subunits β2i and β5i and increased trypsin-like and chymotrypsin-like activity but downregulated MKP5 and VE-cadherin expression and activated p38 MAPK in the heart and LECs (Figures 1 and 5). Conversely, treatment of mouse LECs with losartan (an AT1R antagonist) or epoxomicin (a proteasome inhibitor) markedly reversed the Ang II-induced decreases in MKP5 and VEcadherin protein expression and the activation of p38 MAPK, leading to attenuation of lymphatic vessel hyperpermeability (Figures 5 and 6).…”

“…Degradation of Permeability-Related Proteins in the Heart and in Cultured LECs. Based on our previous data that Ang II infusion markedly increases cardiac proteasome activity and immunoproteasome subunit expression in mice [26,29] and our current results showing that MKP-5, VEcadherin, and p38 MAPK might be important signaling pathways that induce lymphatic hyperpermeability leading to cardiac edema (Figures 1(h)-1(j)) and that these proteins are regulated by the proteasome [30,31], we assessed whether Ang II-induced activation of the proteasome can cause degradation of the proteins MKP-5 and VE-cadherin and activation of p38 MAPK in the heart and LECs in vitro. Consistent with previous data, compared with saline infusion, Ang II infusion mainly increased trypsin-like and chymotrypsin-like activity and the expression of the immunoproteasome catalytic subunits β2i and β5i at both the mRNA and protein levels in the heart (Figures 5(a)-5(c)).…”

Mechanisms and Efficacy of Traditional Chinese Medicine in Heart Failure

“…Gallic acid is a tannin of the genus Paeonia. Gallic acid (PubChem CID: 370) protects cardiac dysfunction by reducing the level of IL-6 and TNF-α in particulate matter-induced rat model (Radan et al, 2019) and ameliorates angiotensin II-induced atrial fibrillation by inhibiting immunoproteasome-mediated PTEN degradation in mice (Han D et al, 2020). Paeonol (PubChem CID: 11092) is another compound in the genus Paeonia, especially Paeonia suffruticosa Andr., which has a cardioprotective effect in epirubicin-induced cardiotoxicity via increasing MicroRNA-1 (miR-1) to suppress the PI3K/AKT/ mTOR and NF-kB signaling pathways (Wu et al, 2018) and reducing inflammatory damage in I/R injury rats (Ma et al, 2016), (Table 5).…”

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway

“…To activate or inhibit autophagy, animals (n = 8 per group) were intraperitoneally injected with the mTOR inhibitor, rapamycin at 4 mg/kg, or with 3-MA at 10 mg/kg daily for 4 weeks (Yang et al 2020(Yang et al , 2021. For proteasome or PTEN inhibition, mice (n = 6 per group) were intraperitoneally injected with epoxomicin at 2.9 mg/kg or VO-OHpic at 10 mg/kg daily for 4 weeks (Han et al 2020;Meng et al 1999). These agents had been obtained from Selleck (Houston, TX, USA) and dissolved in 0.9% saline.…”

“…Therefore, autophagy participated in TACinduced cardiac remodeling in ATGL KO mice. The proteasome complex is highly induced by various hypertrophic stimuli and crucial for regulating autophagy and PTEN stability in the hearts (Cao et al 2019;Chen et al 2019;Han et al 2020;Xie et al 2019;Xie et al 2020;Yan et al 2020). Therefore, we assessed the effect the of ATGL KO on the catalytic subunit expressions and activities in the hearts.…”