Stachydrine Hydrochloride Regulates the NOX2-ROS-Signaling Axis in Pressure-Overload-Induced Heart Failure

Area of Science:

• Cardiovascular Biology
• Pharmacology
• Cellular Physiology

Background:

• Previous studies indicate stachydrine hydrochloride (STA) offers protection against cardiac remodeling.
• The calcium/calmodulin-dependent protein kinase II (CaMKII) pathway is implicated, but STA's precise influence requires further investigation.
• Nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-derived reactive oxygen species (ROS) are hypothesized to activate CaMKII, leading to pathological cardiac remodeling.

Purpose of the Study:

• To investigate the role of the NOX2-ROS signaling axis in STA's cardioprotective effects.
• To elucidate the molecular mechanisms by which STA mitigates cardiac dysfunction.

Main Methods:

• Utilized transverse aortic constriction (TAC)-induced heart failure in mice, phenylephrine-induced hypertrophy in neonatal rat cardiomyocytes, and H2O2-induced oxidative stress in adult mouse cardiomyocytes and H9c2 cells.
• Assessed cardiac function via echocardiography and histological staining.
• Quantified NOX2, ROS, and excitation-contraction coupling using Western blotting, immunofluorescence, and calcium transient recordings.

Main Results:

• STA treatment alleviated ROS and ROS-dependent cardiac fibrosis in TAC mice, improving left ventricular ejection fraction and reducing hypertrophy.
• STA suppressed NOX2 expression and activation in heart failure and cardiomyocyte hypertrophy models.
• STA mitigated NOX2-related cytosolic Ca2+ overload, enhanced contractility, and reduced Ca2+-dependent regulatory protein expression (CaMKII, Ryanodine receptor) in cardiomyocytes under oxidative stress.

Conclusions:

• STA's cardioprotection against pressure overload-induced cardiac remodeling is linked to the inhibition of the NOX2-ROS signaling cascade.
• STA effectively targets the NOX2-ROS pathway to prevent pathological cardiac remodeling and dysfunction.