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Scutellarin ameliorates ischemia/reperfusion-mediated endothelial dysfunction by upregulating cathepsin D expression
Qizhen Zhuang1, Lu Chen1, Wanqian Wu1
1The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
Insights
Scutellarin (SCU) protects against cardiac ischemia/reperfusion (I/R) injury by improving endothelial function. It achieves this by upregulating cathepsin D (CTSD), restoring autophagy-lysosomal pathways, and reducing inflammation and oxidative stress.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Pharmacology
Background:
- Cardiac ischemia/reperfusion (I/R) injury involves endothelial dysfunction and microcirculation impairment.
- Current treatments lack efficacy in addressing the underlying mechanisms of I/R-mediated endothelial dysfunction.
- Scutellarin (SCU), a flavonoid, shows cardiovascular protective effects, but its anti-endothelial dysfunction mechanisms are unexplored.
Purpose of the Study:
- To investigate the efficacy of Scutellarin (SCU) in treating endothelial dysfunction during cardiac I/R injury.
- To elucidate the underlying molecular mechanisms of SCU's protective effects on endothelial cells.
Main Methods:
- Established in vivo (coronary artery ligation) and in vitro (oxygen-glucose deprivation/resupply) models of cardiac I/R injury.
- Administered SCU pretreatment and evaluated its effects on endothelial function, myocardial injury, and cardiac function.
- Assessed markers of oxidative stress, inflammation, nitric oxide bioavailability, and endothelial cell damage.
- Investigated the role of autophagy-lysosomal pathways and cathepsin D (CTSD) in SCU's mechanism of action.
Main Results:
- SCU pretreatment improved vasodilation, reperfusion, cardiac function, and reduced myocardial infarction in I/R models.
- SCU inhibited endothelial cell damage, reactive oxygen species (ROS) accumulation, inflammation, and normalized nitric oxide (NO) and endothelin 1 (ET-1) levels.
- SCU upregulated cathepsin D (CTSD) expression, restoring disrupted autophagy-lysosomal flux.
- CTSD knockdown or inhibition abrogated SCU's protective effects.
Conclusions:
- Scutellarin (SCU) effectively alleviates cardiac I/R-mediated endothelial dysfunction.
- SCU exerts its protective effects by upregulating CTSD, thereby rescuing autophagy-lysosomal function.
- SCU represents a promising therapeutic agent for preventing and treating cardiac I/R injury.
Background:
Endothelial dysfunction-induced microcirculation impairment and the no-reflow phenomenon are the leading causes of cardiac ischemia/reperfusion (I/R) injury. There is an urgent need to elucidate the underlying mechanism of I/R-mediated endothelial dysfunction and to identify effective drugs for treatment. Scutellarin (SCU), a flavonoid compound, has been extensively studied because of its various pharmacological properties, including its potent protective effects on the cardiovascular system. However, the anti-endothelial dysfunction efficacy and mechanisms of action of SCU have not been investigated.
Approach And Results:
An in vivo I/R injury model was established using coronary artery ligation and release. An oxygen-glucose deprivation/oxygen-glucose resupply (OGD/OGR) approach was used to establish an in vitro I/R injury model. We evaluated the effects of SCU on endothelial dysfunction under I/R conditions, both in vivo and in vitro. SCU pretreatment promoted vasodilation and reperfusion of blood flow, inhibited myocardial injury and infarction, and improved cardiac function in I/R rats. Additionally, SCU inhibited cell membrane damage, reactive oxygen species (ROS) accumulation, inflammation, nitric oxide (NO) reduction, endothelin 1 (ET-1) elevation and increase in the expression levels of vascular endothelial growth factor (VEGF) and von willebrand factor (vWF) in endothelial cells. Mechanistically, SCU rescued the lysosomal flow and autophagic flux disrupted by I/R through upregulating cathepsin D (CTSD) levels. Knockdown of CTSD or treatment with the CTSD inhibitor pepstatin A (P.A) abrogated the protective effects of SCU on endothelial cells under I/R conditions.
Conclusion:
We demonstrated that SCU, via upregulation of CTSD levels in endothelial cells, rescued autophagy-lysosomal function and alleviated I/R-mediated endothelial dysfunction. Thus, SCU is a potential therapeutic drug for the prevention and treatment of cardiac I/R injury.
