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Minimal Invasive Surgical Procedure of Inducing Myocardial Infarction in Mice
Published on: May 4, 2015
ROS-Suppression Nanoplatform Combined Activation of STAT3/Bcl-2 Pathway for Preventing Myocardial Infarction in Mice
Nan Hu1,2, Meng Sun1,2,3, Nan Lv4
1Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, 99 Longcheng Street, Taiyuan 030032, China.
Abstract:
Myocardial infarction (MI) is the leading cause of death worldwide. The most effective way to treat myocardial infarction is to rescue ischemic cardiomyocytes. After an ischemic event, the overproduction of reactive oxygen species (ROS) is a key driver of myocardial injury. The produced ROS affects mitochondrial function and induces apoptosis in cardiomyocytes. This was accomplished by constructing platelet-membrane-encapsulated ROS-responsive drug-releasing nanoparticles (PMN@NIC-MalNPs) to deliver malonate and niclosamide (NIC). The results revealed that PMN@NIC-MalNPs degraded and released malonate and niclosamide in a high-level ROS microenvironment, effectively reducing the oxidative stress and apoptosis rate. By enhancing basal mitochondrial oxygen consumption rate (OCR), adenosine triphosphate (ATP) production, and spare respiratory capacity (SRC) in vitro, reduced the oxidative stress levels and restored mitochondrial function. In vivo studies revealed that the PMN@NIC-MalNPs improved cardiac dysfunction, inhibited succinate dehydrogenase (SDH) activity, increased ATP production, and reduced the myocardial infarct size in myocardial infarction model mice. Further, transcriptome analysis and Western blot revealed that PMN@NIC-MalNPs prevented apoptosis by activating the expressions of the signal transducer and activator of transcription 3 (STAT3) and Bcl-2, and inhibiting the expression of Bax. Thus, this study provides a novel therapeutic solution for treating myocardial infarction and predicting the viability of an antioxidant and antiapoptotic therapeutic solution in the treatment of myocardial injury.
Insights
This study introduces novel nanoparticles that deliver drugs to reduce oxidative stress and cell death after heart attacks. These nanoparticles improve heart function and reduce damage in myocardial infarction models.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanomedicine
Background:
- Myocardial infarction (MI) is a leading global cause of death, primarily due to cardiomyocyte injury from reactive oxygen species (ROS).
- Elevated ROS levels impair mitochondrial function and trigger apoptosis in heart cells, exacerbating myocardial damage.
- Current treatments for MI focus on restoring blood flow, but effective strategies to mitigate ROS-induced injury are crucial.
Purpose of the Study:
- To develop and evaluate ROS-responsive nanoparticles for targeted drug delivery to rescue ischemic cardiomyocytes.
- To investigate the therapeutic potential of malonate and niclosamide (NIC) delivered via these nanoparticles in treating myocardial infarction.
- To assess the impact of the nanoparticles on oxidative stress, mitochondrial function, apoptosis, and cardiac performance.
Main Methods:
- Construction of platelet-membrane-encapsulated ROS-responsive nanoparticles (PMN@NIC-MalNPs) carrying malonate and niclosamide.
- In vitro assessment of nanoparticle degradation, drug release in high-ROS environments, and effects on cardiomyocyte oxidative stress and mitochondrial function (OCR, ATP, SRC).
- In vivo evaluation in myocardial infarction mouse models, assessing cardiac function, infarct size, mitochondrial enzyme activity (SDH), and molecular markers of apoptosis (STAT3, Bcl-2, Bax) via transcriptome analysis and Western blot.
Main Results:
- PMN@NIC-MalNPs effectively released malonate and niclosamide in high-ROS conditions, significantly reducing oxidative stress and apoptosis rates in vitro.
- In vitro studies demonstrated enhanced mitochondrial respiration (OCR, ATP production, SRC) and restored mitochondrial function.
- In vivo studies showed improved cardiac function, reduced infarct size, inhibited SDH activity, increased ATP levels, and prevention of apoptosis through STAT3 and Bcl-2 activation, and Bax inhibition.
Conclusions:
- PMN@NIC-MalNPs represent a novel and effective therapeutic strategy for myocardial infarction by delivering antioxidant and antiapoptotic agents.
- The ROS-responsive drug delivery system successfully mitigates oxidative stress and restores mitochondrial function in cardiomyocytes.
- This approach offers a promising therapeutic solution for myocardial injury, highlighting the potential of targeted nanomedicine in cardiovascular disease treatment.
