Aliskiren attenuates cardiac dysfunction by modulation of the mTOR and apoptosis pathways

Abstract

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg Á kg-1 Á day-1) for 4 weeks, with or without ALS treatment at 20 mg Á kg-1 Á day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Protective Effect of Patchouli Alcohol Against SH-SY5Y Cell Injury Induced by Aβ25-35via the Reduction of Oxidative Stress and Apoptosis

“…35 The mTOR can be directly activated by Akt, and also plays an important role in the metabolism, growth, and apoptosis of the nerve cells. 36 It was found that PA can inhibit the autophagy in hippocampus, repair synapses, and restore the autophagy flux by activating the mTOR signaling pathway, with an antidepressant effect on rats with chronic unpredictable mild stress. 37 The results of this study also showed that compared with those in the normal control group, p-Akt and p-mTOR protein levels in the Aβ 25-35 -induced injury group were significantly reduced ( P < .01), and compared with those in the Aβ 25-35 -induced injury group, p-Akt and p-mTOR protein levels in Aβ 25-35 -induced SH-SY5Y cells increased significantly in the different PA-treated groups ( P < .05 or P < .01, Figure 6).…”

Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway

“…( Bahadir et al, 2018 ), and aliskiren (20 mg/kg/day; p.o.) ( Zhao et al, 2020 ), respectively. Groups from 3 to 7 received their respective treatments starting from day 13 after the first dose of CFA, and then continued for 3 weeks.…”

Protein kinases in cardiovascular diseases

“…Several drugs targeting these functional protein kinases have been developed and tested. In the model of cardiac hypertrophy, mibefradil, rapamycin, and aliskiren are found to inhibit PI3K/Akt/mTOR-mediated autophagy to alleviate CM hypertrophy and reverse cardiac remodeling [31–33] . Similarly, metoprolol and bisoprolol inhibit PKC to reverse cardiac hypertrophy [34] …”

“…In the model of cardiac hypertrophy, mibefradil, rapamycin, and aliskiren are found to inhibit PI3K/Akt/mTOR-mediated autophagy to alleviate CM hypertrophy and reverse cardiac remodeling. [31][32][33] Similarly, metoprolol and bisoprolol inhibit PKC to reverse cardiac hypertrophy. [34] Atherosclerosis Atherosclerosis is progressive inflammatory progress and the primary cause of myocardial infarction (MI) and stroke.…”