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The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to
Lei Qi1, Jia Yi1, Yuntian Shen1
1Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu Province 226001, People's Republic of China.
Abstract:
Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities-apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis-while microcirculatory disturbances cause the "no-reflow" phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the "energy-death-inflammation" network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.
Insights
Myocardial ischemia involves complex cell damage pathways. New therapies target energy, death, and inflammation networks for better heart repair and outcomes.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Myocardial ischemic injury is a complex process involving energy metabolism, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammation.
- Reperfusion can worsen injury via reactive oxygen species (ROS), mitochondrial permeability transition pore (mPTP) opening, and NLRP3 inflammasome activation.
- Endoplasmic reticulum (ER) stress contributes to apoptosis, creating a cycle with oxidative stress and inflammation, leading to diverse cell death types.
Purpose of the Study:
- To review the multifaceted pathological cascade of myocardial ischemic injury.
- To explore current and emerging therapeutic strategies targeting key molecular pathways.
- To highlight the shift towards multi-target interventions and precision medicine.
Main Methods:
- Review of existing literature on myocardial ischemia pathophysiology and therapeutic interventions.
- Analysis of molecular mechanisms including energy metabolism, cell death pathways, and inflammatory responses.
- Categorization of therapeutic approaches: conditioning, cell death inhibition, metabolic/mitochondrial support, regenerative medicine, and precision medicine.
Main Results:
- Ischemia-reperfusion injury involves a complex interplay of metabolic, oxidative, inflammatory, and cell death pathways.
- Therapeutic strategies are evolving from revascularization to multi-target interventions including ischemic conditioning, cell death inhibitors, metabolic modulators, and regenerative approaches.
- Precision medicine utilizing multi-omics and AI, alongside nanocarrier drug delivery, represents a future direction.
Conclusions:
- Targeting the interconnected 'energy-death-inflammation' network is crucial for advancing myocardial ischemia treatment.
- Future therapies should focus on systemic repair and improved clinical outcomes through integrated approaches.
- Personalized medicine and advanced drug delivery systems hold promise for more effective myocardial protection.
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