Do any of your stroke medical 'professionals' look at this and say; Let's see if this would help post stroke? NO? So you DON'T have any professionals out there, do you?
But I guess you knew that already since they did nothing with exosomes, did they? 14 years of incompetency and I bet that continues for another 14 years!
exosomes
(55 posts to March 2011) Lymph Node Exosomes Delivery Attenuates Myocardial Ischemia-Reperfusion Injury via Regulating PTEN-PI3K/Akt Pathway Mediated Myocardiocyte Apoptosis
Authors Qiao S , Wu B, Chen L, Ma L, Wang Y, Xu B, Gu R
Received 19 December 2024
Accepted for publication 4 April 2025
Published 17 April 2025
Volume 2025:20 Pages 4967—4981
DOI https://doi.org/10.2147/IJN.S512135
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication:
Professor Eng San Thian
Shuaihua Qiao,1,2,* Baochuan Wu,3,* Lin Chen,3 Lingyu Ma,1 Yi Wang,3 Biao Xu,1 Rong Gu3
1Department
of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of
Medical School, Nanjing University, Nanjing, Jiangsu Province, People’s
Republic of China; 2School of Cardiovascular and Metabolic
Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s
College London, London, UK; 3Department of Cardiology,
Nanjing Drum Tower Hospital Clinical College of Nanjing University of
Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China
*These authors contributed equally to this work
Correspondence:
Rong Gu; Biao Xu, Department of Cardiology, Nanjing Drum Tower
Hospital, Affiliated Hospital of Medical School, Nanjing University, No.
321 Zhongshan Road, Nanjing, Jiangsu Province, 210008, People’s
Republic of China, Tel/Fax +86-25-68182812, Email gurong.nju@163.com; xubiao62@nju.edu.cn
Background:
Ischemia/reperfusion (I/R) injury following acute myocardial infarction
(AMI) induces myocardial apoptosis. Exosomes from KLF2-overexpressing
endothelial cells (KLF2-EXO) dampened the effects of I/R injury. The
intra-lymph node drainage pathway provides an alternative method to
study the therapeutic effects of exosomes. In this study, we explored
the role of intra-lymph node injection of KLF2-EXO in myocardial I/R
injury.
Method and Result: Exosomes were isolated
from KLF2-overexpressing mouse coronary endothelial cell supernatant via
gradient centrifugation. The mice were subjected to ischemia and
reperfusion, and an appropriate dosage of KLF2-EXO was administrated via
intra-inguinal lymph node injection. KLF2-EXO attenuated I/R injury and
alleviated myocardiocyte apoptosis in heart tissue, and
immunofluorescence staining indicated KLF2-EXO could be transferred into
the heart. MiRNA-sequencing of KLF2-EXO implicated that miRNA-486-5p
(miR-486-5p) was a potent candidate mediator that inhibited
myocardiocyte apoptosis, and the miR-486-5p antagomir reversed the
effect. Further bioinformatics analysis and confirmation experiments
revealed that PTEN functions as a downstream target and that the PTEN-
PI3K/Akt pathway participates in the regulation of cardiomyocyte
apoptosis.
Conclusion: Our data demonstrated that
intra-lymph node injection of KLF2-EXO attenuated myocardial I/R injury
in mice by delivering miR-486-5p to target PTEN- PI3K/Akt pathway, which
restrained myocardiocyte apoptosis. KLF2-EXO may serve as an
alternative therapy for myocardial I/R injury.
Keywords:
intra lymph node injection, Krüppel-like factor 2-overexpressing mouse
coronary endothelial cells, exosomes, myocardial ischemia/reperfusion
injury, myocardiocyte apoptosis, miRNA-486-5p
Graphical Abstract:
Introduction
Acute myocardial infarction (AMI) is a deadly disease worldwide due
to decreased coronary blood flow, resulting in an insufficient oxygen
supply to the heart.1
Reperfusion therapy, including fibrinolytic drugs and percutaneous
coronary intervention (PCI), for AMI patients can recover blood flow to
the ischemic myocardium and thus reduce the infarct size.2 However, reperfusion triggers further myocardial damage known as reperfusion injury.3
The ischemia/reperfusion (I/R) process induces various cascade
reactions, including myocardiocyte apoptosis, neutrophil and monocyte
activation and recruitment, necrotic cell clearance, tissue repair, and
so on.4–6 Many studies have focused on exploring an effective method to sustain an optimal but not an excessive inflammatory response.7–9 Reducing myocardiocyte apoptosis is another way to repair the myocardium and improve its prognosis.10
Endothelial cells (ECs) play a vital role in vascular homeostasis as major functional coordinators.11,12
Under pathological stress, ECs highly express Krüppel-Like Factor 2
(KLF2) through mechanosensory complex activation and adapt to laminar
blood flow.13 Previous studies have shown that KLF2-transduced ECs mediate monocyte/macrophage polarization during atherosclerosis.14
However, the effect of KLF2-overexpressing endothelial cells on
myocardial apoptosis following myocardial I/R injury remains unclear.
Exosomes, small particles with a diameter of approximately 50–150 nm,
are potential biological mediators of therapeutic effects in diseases
via their participation in intercellular communication.15
Compared with cell therapy, exosomes have many benefits, including
immunological inertness, nontoxicity, biocompatibility, escape from
phagocytosis, and capacity to pass through biological barriers.16 In a recent study, exosomes derived from KLF2-transduced ECs inhibited atherosclerotic lesion formation in the aortas of ApoE−/− mice.14
Coincidentally, our previous study also indicated that extracellular
vesicles derived from KLF2-transduced endothelial cells ameliorate
myocardial I/R injury by inhibiting Ly6Chigh monocyte recruitment9 and attenuating left ventricular dysfunction in a dilated cardiomyopathy (DCM) mouse model.17
However, whether exosomes from KLF2-overexpressing ECs can reduce
myocardial apoptosis in myocardial I/R injury remains to be explored.
The lymphatic system is part of the vertebrate immune system and is complementary to the circulatory system.18
The lymph is a clear fluid in the lymphatic vessels back to the heart
for recirculation, which transports cells and extracellular vesicles
from the lymph nodes into the bones and heart.19
The inguinal lymph nodes are in the groin area and are classified as
superficial or deep; the former can be found after peeling within the
femoral triangle in mice, and the latter is medial to the femoral vein. A
Technetium-99 m radiolabelled nano colloid or blue dye is also often
injected locally to assist with the visualization of nodes after
incision.20
Therefore, the inguinal lymph node-lymph-heart axis can be used to
transport therapeutic exosomes. We chose intra-inguinal lymph node
(iILN) injection over intracoronary (IC), intravenous (IV), or
intramyocardial (IM) injections because of its operability and safety.
However, the detailed mechanisms underlying the treatment of myocardial
I/R injury with iILN injections remain elusive.
In this study, we isolated exosomes from KLF2-overexpressing mouse
coronary endothelial cells (MCAECs) (KLF2-EXO), and injected them into
mice after myocardial I/R injury. We found KLF2-EXO could restrain
myocardiocyte apoptosis and improve heart function, mediated via
miRNA-486-5p (miR-486-5p) by targeting the PTEN- PI3K/Akt pathway.
Authors Qiao S , Wu B, Chen L, Ma L, Wang Y, Xu B, Gu R
Received 19 December 2024
Accepted for publication 4 April 2025
Published 17 April 2025 Volume 2025:20 Pages 4967—4981
DOI https://doi.org/10.2147/IJN.S512135
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Eng San Thian
Shuaihua Qiao,1,2,* Baochuan Wu,3,* Lin Chen,3 Lingyu Ma,1 Yi Wang,3 Biao Xu,1 Rong Gu3
1Department
of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of
Medical School, Nanjing University, Nanjing, Jiangsu Province, People’s
Republic of China; 2School of Cardiovascular and Metabolic
Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s
College London, London, UK; 3Department of Cardiology,
Nanjing Drum Tower Hospital Clinical College of Nanjing University of
Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China
*These authors contributed equally to this work
Correspondence:
Rong Gu; Biao Xu, Department of Cardiology, Nanjing Drum Tower
Hospital, Affiliated Hospital of Medical School, Nanjing University, No.
321 Zhongshan Road, Nanjing, Jiangsu Province, 210008, People’s
Republic of China, Tel/Fax +86-25-68182812, Email gurong.nju@163.com; xubiao62@nju.edu.cn
Background:
Ischemia/reperfusion (I/R) injury following acute myocardial infarction
(AMI) induces myocardial apoptosis. Exosomes from KLF2-overexpressing
endothelial cells (KLF2-EXO) dampened the effects of I/R injury. The
intra-lymph node drainage pathway provides an alternative method to
study the therapeutic effects of exosomes. In this study, we explored
the role of intra-lymph node injection of KLF2-EXO in myocardial I/R
injury.
Method and Result: Exosomes were isolated
from KLF2-overexpressing mouse coronary endothelial cell supernatant via
gradient centrifugation. The mice were subjected to ischemia and
reperfusion, and an appropriate dosage of KLF2-EXO was administrated via
intra-inguinal lymph node injection. KLF2-EXO attenuated I/R injury and
alleviated myocardiocyte apoptosis in heart tissue, and
immunofluorescence staining indicated KLF2-EXO could be transferred into
the heart. MiRNA-sequencing of KLF2-EXO implicated that miRNA-486-5p
(miR-486-5p) was a potent candidate mediator that inhibited
myocardiocyte apoptosis, and the miR-486-5p antagomir reversed the
effect. Further bioinformatics analysis and confirmation experiments
revealed that PTEN functions as a downstream target and that the PTEN-
PI3K/Akt pathway participates in the regulation of cardiomyocyte
apoptosis.
Conclusion: Our data demonstrated that
intra-lymph node injection of KLF2-EXO attenuated myocardial I/R injury
in mice by delivering miR-486-5p to target PTEN- PI3K/Akt pathway, which
restrained myocardiocyte apoptosis. KLF2-EXO may serve as an
alternative therapy for myocardial I/R injury.
Keywords:
intra lymph node injection, Krüppel-like factor 2-overexpressing mouse
coronary endothelial cells, exosomes, myocardial ischemia/reperfusion
injury, myocardiocyte apoptosis, miRNA-486-5p
Graphical Abstract:
Introduction
Acute myocardial infarction (AMI) is a deadly disease worldwide due to decreased coronary blood flow, resulting in an insufficient oxygen supply to the heart.1 Reperfusion therapy, including fibrinolytic drugs and percutaneous coronary intervention (PCI), for AMI patients can recover blood flow to the ischemic myocardium and thus reduce the infarct size.2 However, reperfusion triggers further myocardial damage known as reperfusion injury.3 The ischemia/reperfusion (I/R) process induces various cascade reactions, including myocardiocyte apoptosis, neutrophil and monocyte activation and recruitment, necrotic cell clearance, tissue repair, and so on.4–6 Many studies have focused on exploring an effective method to sustain an optimal but not an excessive inflammatory response.7–9 Reducing myocardiocyte apoptosis is another way to repair the myocardium and improve its prognosis.10
Endothelial cells (ECs) play a vital role in vascular homeostasis as major functional coordinators.11,12 Under pathological stress, ECs highly express Krüppel-Like Factor 2 (KLF2) through mechanosensory complex activation and adapt to laminar blood flow.13 Previous studies have shown that KLF2-transduced ECs mediate monocyte/macrophage polarization during atherosclerosis.14 However, the effect of KLF2-overexpressing endothelial cells on myocardial apoptosis following myocardial I/R injury remains unclear.
Exosomes, small particles with a diameter of approximately 50–150 nm, are potential biological mediators of therapeutic effects in diseases via their participation in intercellular communication.15 Compared with cell therapy, exosomes have many benefits, including immunological inertness, nontoxicity, biocompatibility, escape from phagocytosis, and capacity to pass through biological barriers.16 In a recent study, exosomes derived from KLF2-transduced ECs inhibited atherosclerotic lesion formation in the aortas of ApoE−/− mice.14 Coincidentally, our previous study also indicated that extracellular vesicles derived from KLF2-transduced endothelial cells ameliorate myocardial I/R injury by inhibiting Ly6Chigh monocyte recruitment9 and attenuating left ventricular dysfunction in a dilated cardiomyopathy (DCM) mouse model.17 However, whether exosomes from KLF2-overexpressing ECs can reduce myocardial apoptosis in myocardial I/R injury remains to be explored.
The lymphatic system is part of the vertebrate immune system and is complementary to the circulatory system.18 The lymph is a clear fluid in the lymphatic vessels back to the heart for recirculation, which transports cells and extracellular vesicles from the lymph nodes into the bones and heart.19 The inguinal lymph nodes are in the groin area and are classified as superficial or deep; the former can be found after peeling within the femoral triangle in mice, and the latter is medial to the femoral vein. A Technetium-99 m radiolabelled nano colloid or blue dye is also often injected locally to assist with the visualization of nodes after incision.20 Therefore, the inguinal lymph node-lymph-heart axis can be used to transport therapeutic exosomes. We chose intra-inguinal lymph node (iILN) injection over intracoronary (IC), intravenous (IV), or intramyocardial (IM) injections because of its operability and safety. However, the detailed mechanisms underlying the treatment of myocardial I/R injury with iILN injections remain elusive.
In this study, we isolated exosomes from KLF2-overexpressing mouse coronary endothelial cells (MCAECs) (KLF2-EXO), and injected them into mice after myocardial I/R injury. We found KLF2-EXO could restrain myocardiocyte apoptosis and improve heart function, mediated via miRNA-486-5p (miR-486-5p) by targeting the PTEN- PI3K/Akt pathway.
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