A Novel Compound, Tanshinol Borneol Ester, Ameliorates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Oxidative Stress via the mTOR/β-TrCP/NRF2 Pathway

Abstract

Tanshinol borneol ester (DBZ) exerts anti-atherosclerotic and anti-inflammatory effects. However, its effects on cardiac hypertrophy are not well understood. In this work, we investigated the treatment effects and potential mechanisms of DBZ on the hypertrophic heart under oxidative stress and endoplasmic reticulum (ER) stress. A hypertrophic model was established in rats using transverse-aortic constriction (TAC) surgery and in neonatal rat cardiomyocytes (NRCMs) using angiotensin II (Ang II). Our results revealed that DBZ remarkably inhibited oxidative stress and ER stress, blocked autophagy flow, and decreased apoptosis in vivo and in vitro through nuclear NRF2 accumulation, and enhanced NRF2 stability via regulating the mTOR/β-TrcP/NRF2 signal pathway. Thus, DBZ may serve as a promising therapeutic for stress-induced cardiac hypertrophy.

Neutrophil membrane-camouflaged nanoparticles alleviate inflammation and promote angiogenesis in ischemic myocardial injury

“…As previously described, Coomassie blue staining and Western blotting were performed to confirm the presence of neutrophil membrane–associated proteins [ 26 ]. Briefly, the neutrophil lysate (NL), neutrophil vesicles (NVs), and NM-NPs were lysed on ice for 10 min in lysis buffer (Solarbio, Beijing, China).…”

Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

“…[103][104][105][106] Acting through mTOR, tanshione IIA promoted the transcription and stability of NRF2, and its antiapoptotic effects were dampened by NRF2 silencing. 34 Additionally, in human pluripotent stem cell-derived cardiomyocytes, QLQX increased Ca 2+ spark frequency, amplitude and duration, indicative of enhanced Ca 2+ release. 107 Similar effects have been reported with digitalis and other plant-derived compounds with positive inotropic actions.…”

“…6,7,29,32 Both pathways can exert important cardioprotective effects, depending on the duration and severity of cardiac stress (Figures 1 and 2). During marked abrupt stress, cardioprotection relies on upregulation of the PI3K-Akt-mTORHIF-1α-PGC-1α-NRF2 pathway, which act to ameliorate autophagic hyperactivation and the deleterious accumulation of autophagosomes and to promote mitochondrial biogenesis and antioxidant defenses [33][34][35][36] ; yet, such signalling is deleterious if it is sustained for long periods. 7,30,37 Conversely, upregulation of SIRT1 and AMPK may be counterproductive during abrupt marked stress, 38 but during sustained measured stress (as is typically the case in cardiomyopathy), prolonged SIRT1-AMPK-PGC-1α signalling exerts highly favourable effects on cardiomyocyte function and viability.…”

“…30,39 Short-term upregulation of mTOR, PPARγ, RXRα and YY1 (and their downstream effector, NRF2) suppresses excessive autophagosome formation and exerts cardioprotective effects in acute ischaemia or pressure overload. 34,[66][67][68] However, prolonged upregulation of PGC-1α, RXRα and PPARγ leads to mitochondrial oxidative dysfunction, lipid accumulation, maladaptive hypertrophy and cardiomyopathy, 50,69,70 and experimental diabetic cardiomyopathy is alleviated by PPARγ silencing. 57 mTOR and PPARγ also act to upregulate NRF2, 41 and sustained NRF2 activation produces excessive reductive stress with adverse effects on cardiomyopathy.…”

“…In contrast, during acute stress, PGC‐1α coactivates a heterodimer of RXRα and PPARγ under the influence of the transcription factor yin‐yang 1 (YY1), a target of mTOR and a promoter of mitochondrial biogenesis and oxidative functions 30,39 . Short‐term upregulation of mTOR, PPARγ, RXRα and YY1 (and their downstream effector, NRF2) suppresses excessive autophagosome formation and exerts cardioprotective effects in acute ischaemia or pressure overload 34,66–68 . However, prolonged upregulation of PGC‐1α, RXRα and PPARγ leads to mitochondrial oxidative dysfunction, lipid accumulation, maladaptive hypertrophy and cardiomyopathy, 50,69,70 and experimental diabetic cardiomyopathy is alleviated by PPARγ silencing 57 .…”