DR1-CSE/H₂S pathway upregulates autophagy and inhibits H9C2 cells damage induced by high glucose

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Molecular Pharmacology

Background:

• High glucose (HG) induces cardiomyocyte damage, impacting cardiovascular health.
• Hydrogen sulfide (H2S) plays a role in regulating cardiomyocyte autophagy.
• Dopamine 1 receptors (DR1) are implicated in cardiovascular regulation, but their role in HG-induced damage is unclear.

Purpose of the Study:

• To investigate if DR1 activation mitigates HG-induced cardiomyocyte damage by modulating H2S production and autophagy.
• To elucidate the signaling pathways involved, specifically focusing on the CSE/H2S axis and mTOR signaling.

Main Methods:

• Primary cardiomyocyte cultures were subjected to high glucose conditions.
• Treatment with DR1 agonist (SKF38393), H2S donor (NaHS), CSE inhibitor (PPG), autophagy inhibitor (3MA), AMPK agonist (AICAR), and mTOR inhibitor (Rapamycin).
• Assessment of cell viability, apoptosis, autophagy markers (Bcl-2, Beclin1, LC3 II/I, autophagosomes, P62), and signaling proteins (caspase-3, caspase-9, cytochrome c, mTOR).

Main Results:

• HG reduced DR1, CSE expression, and H2S levels, leading to decreased cell viability and increased apoptosis.
• SKF38393 and NaHS reversed HG-induced damage by increasing H2S and CSE, promoting autophagy, and inhibiting mTOR.
• Inhibition of CSE or autophagy abolished the protective effects of SKF38393.
• AICAR and Rapamycin mimicked the effects of SKF38393 on autophagy and mTOR.

Conclusions:

• DR1 activation protects cardiomyocytes against HG-induced damage.
• This protection is mediated through the upregulation of the cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) pathway.
• DR1 enhances autophagy and inhibits mTOR activation, thereby reducing cardiomyocyte injury.