Ophiopogonin D Attenuates Doxorubicin-Induced Autophagic Cell Death by Relieving Mitochondrial Damage In Vitro and In Vivo

Abstract

It has been reported that ophiopogonin D (OP-D), a steroidal glycoside and an active component extracted from Ophiopogon japonicas, promotes antioxidative protection of the cardiovascular system. However, it is unknown whether OP-D exerts protective effects against doxorubicin (DOX)-induced autophagic cardiomyocyte injury. Here, we demonstrate that DOX induced excessive autophagy through the generation of reactive oxygen species (ROS) in H9c2 cells and in mouse hearts, which was indicated by a significant increase in the number of autophagic vacuoles, LC3-II/LC3-I ratio, and upregulation of the expression of GFP-LC3. Pretreatment with OP-D partially attenuated the above phenomena, similar to the effects of treatment with 3-methyladenine. In addition, OP-D treatment significantly relieved the disruption of the mitochondrial membrane potential by antioxidative effects through downregulating the expression of both phosphorylated c-Jun N-terminal kinase and extracellular signal-regulated kinase. The ability of OP-D to reduce the generation of ROS due to mitochondrial damage and, consequently, to inhibit autophagic activity partially accounts for its protective effects in the hearts against DOX-induced toxicity.

Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress

“…OPD is protective, serving as an antioxidant against H 2 O 2 -induced endothelial injury, and it displays mild anti-apoptotic properties [28] . OPD is also protective against doxycycline (DOX)-induced autophagy in cardiomyocytes by inhibiting DOX-induced activation of JNK and ERK1/2, resulting in ROS scavenging and reduced oxidative stress [29] . Although the CYP2J3/EETs system and ER stress-associated pathways are both vital to cardiovascular diseases, the underlying mechanism of the beneficial effects of OPD on cardiac myocytes via CYP2J3 is unknown.…”

Renal 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion

“…20 Therefore, a possible mechanism to explain how knocking out CNPase protects against IR-induced AKI is that CNPase deletion marks malfunctioning mitochondria for rapid autophagy (mitophagy), whereas in the presence of CNPase, malfunctioning mitochondria continue to exist, malfunction, and cause cellular injury. Consistent with this hypothesis, recent studies show that (1) mitochondrial damage is a major stimulus for autophagy, [6][7][8] (2) renal autophagy protects against IRinduced AKI, [9][10][11][12][13][14][15][16] and (3) insufficient autophagy contributes to organ failure. 17 To explore this mitochondria hypothesis, we conducted a detailed analysis of mitochondria and autophagy in kidneys from CNPase , and AKI CNPase 2/2 mice.…”

“…Opening of mPTPs causes mitochondria damage, 5 and mitochondrial damage is a stimulus for autophagy. [6][7][8] Renal autophagy protects against AKI, [9][10][11][12][13][14][15][16] and insufficient autophagy contributes to organ failure. 17 Therefore, it is conceivable that 29,39-cAMP, by increasing autophagy, protects against AKI.…”

Pixantrone, a new anticancer drug with the same old cardiac problems? An in vitro study with differentiated and non-differentiated H9c2 cells

“…For that reason, our results will be compared with the published data of other acknowledged cardiotoxic anticancer drugs, DOX and MTX, in in vitro models. Non-differentiated H9c2 cells exposed to 1 μM DOX at several time points (between 0 and 48 h) evidenced an increase in cell death with increasing time of exposure, evaluated through phase contrast microscopy (Zhang et al ., 2015). Regarding MTX, our group assessed the cytotoxicity of 5 μM and 2 μM MTX in differentiated H9c2 cells.…”

“…In non-differentiated H9c2 cells, DOX elicited mitochondrial dysfunction as seen through the MTT reduction assay, following a 24-h exposure to 0.2, 1 and 5 μM (Zhang et al ., 2015). Regarding MTX, also in non-differentiated H9c2 cells, it led to a time- and concentration-dependent cytotoxicity (Rossato et al ., 2013).…”