Ophiopogonin D: Is It Bad for Your Heart?

Key Findings

This study demonstrated that Ophiopogonin D' (OPD'), a compound derived from Ophiopogon japonicus, triggers mitochondrial damage and cardiotoxicity in AC16 cardiomyocytes via dysregulation of the PINK1/Parkin signaling pathway. At concentrations ≥2 μM, OPD' reduced cell viability (p<0.01) and increased lactate dehydrogenase (LDH) release (p<0.05), indicating cytotoxicity. OPD' induced mitophagy, evidenced by elevated mitochondrial LC3-II/LC3-I ratios (p<0.01), and caused mitochondrial dysfunction, including reduced membrane potential (ΔΨm) and PGC-1α expression (p<0.05). It also activated oxidative stress (increased ROS, p<0.01) and apoptosis (pyknosis, reduced Bcl-2, p<0.05). Inhibiting mitophagy mitigated these effects, suggesting the PINK1/Parkin pathway mediates OPD'-induced toxicity.

Study Design

This in vitro observational study used human AC16 cardiomyocytes treated with OPD' at 0, 1, 2, 4, or 8 μM for 24 or 48 hours. Key assays included MTT for viability, flow cytometry for apoptosis, JC-1 staining for mitochondrial membrane potential (MMP), and Western blotting for protein markers (e.g., LC3, PINK1, Parkin, PGC-1α, Nrf2, HO-1, Bcl-2). The study duration was 48 hours, with time- and dose-dependent effects analyzed. No sample size calculations were provided, but experiments were repeated ≥3 times.

Dosage & Administration

OPD' was administered at concentrations of 2 μM, 4 μM, and 8 μM in cell culture medium. Treatments lasted 24 or 48 hours. The study compared these doses to controls (0 μM) to assess cytotoxicity and pathway activation.

Results & Efficacy

• Cell viability: 2 μM OPD' reduced viability by ~20% at 24 hours (p<0.01) and ~40% at 48 hours (p<0.01).
• LDH release: Significant increases at 2 μM (p<0.05) and 8 μM (p<0.01) after 48 hours.
• Mitophagy: Mitochondrial LC3-II/I ratio increased 2.5-fold at 8 μM (p<0.01).
• Oxidative stress: ROS levels rose by 150% at 8 μM (p<0.01), while Nrf2 and HO-1 expression decreased.
• Apoptosis: Pyknosis increased 3-fold at 8 μM (p<0.01), with a 50% reduction in Bcl-2 (p<0.05).
• PINK1/Parkin activation: OPD' promoted Parkin translocation to mitochondria and phosphorylation of PINK1, indicating pathway activation.

Limitations

• In vitro model: Results may not translate to in vivo systems or human physiology.
• Short duration: Effects observed within 48 hours; long-term impacts are unknown.
• Mechanistic focus: While the PINK1/Parkin pathway was implicated, other mechanisms (e.g., inflammation) were not explored.
• No clinical data: Study lacks human trials or animal models to validate findings.

Clinical Relevance

OPD', a component of Shenmai injection (used for cardiovascular and cancer treatment), exhibits dose-dependent cardiotoxicity in this model. Users should exercise caution with OPD'-containing supplements, particularly those with pre-existing cardiac conditions. The study highlights mitophagy as a potential therapeutic target to mitigate OPD' toxicity, though inhibitors (e.g., 3-MA) require further validation. Clinicians may consider monitoring mitochondrial health in patients using Ophiopogon japonicus-derived therapies. However, results are preliminary and cannot yet guide human dosing or interventions.

Note: This analysis is limited to the provided study details (PubMed ID: 35905946). Full conclusions require peer replication and in vivo/clinical research.