Dataset Information

Bone Morphogenetic Protein 9 Protects against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics

ABSTRACT: We investigated the impact of both BMP9 deficiency and replenishment on the pathogenesis of MI in mice. Our results showed an aggravated pathological phenotype of MI in BMP9 knockout (KO) mice, which can be alleviated by replenishment of BMP9. Therefore, we further investigated the mechanism whereby BMP9 protects against MI-induced cardiac damage and dysfunction via its multiple actions among the liver, lymph, and heart.

ORGANISM(S): Mus Musculus

SUBMITTER: Zhuofeng Lin

PROVIDER: PXD051517 | iProX | Wed Apr 17 00:00:00 BST 2024

REPOSITORIES: iProX

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Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

Duan Zikun Z Huang Zhouqing Z Lei Wei W Zhang Ke K Xie Wei W Jin Hua H Wu Maolan M Wang Ningrui N Li Xiaokun X Xu Aimin A Zhou Hao H Wu Fan F Li Yulin Y Lin Zhuofeng Z

Circulation 20240924 21

<h4>Background</h4>BMP9 (bone morphogenetic protein 9) is a member of the TGF-β (transforming growth factor β) family of cytokines with pleiotropic effects on glucose metabolism, fibrosis, and lymphatic development. However, the role of BMP9 in myocardial infarction (MI) remains elusive.<h4>Methods</h4>The expressional profiles of BMP9 in cardiac tissues and plasma samples of subjects with MI were determined by immunoassay or immunoblot. The role of BMP9 in MI was determined by evaluating the im ...[more]

PMID: 39315433

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Project description:Background: Guided by long-term safety data for AAV5 in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieve therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. Methods & Results: In a first biodistribution study, AAV5 (11013 vector genomes; vgs) - carrying the reporter gene luciferase (luc) - achieved broad and homogenous transduction of the left ventricle (LV) of healthy German farm pigs 30 days after percutaneous catheter-based retrograde intravenous delivery (CRID), as measured by vector genome and luc mRNA assessments. Both its myocardial and extra-cardiac distribution patterns were advantageous compared to AAV9-luc and AAV6-luc. Using the cardioprotective human gene S100A1 (hS100A1) in a subsequent therapy study, effective myocardial transduction with AAV5-hS100A1 (11013 vgcs) by CRID prevented LV myocardial infarction (MI) enlargement and improved systolic contractile performance after 3 months in a porcine model with chronic post-MI cardiac dysfunction, as assessed by serial cardiac magnetic resonance imaging. The use of a cardiac-biased promoter ensured cardiac-targeted hS100A1 expression without signs of clinical toxicity, as shown by RT-PCR analysis, clinical chemistry and blood count. A previously unknown anti-inflammatory effect of hS100A1 in damaged myocardium, detected and linked to the therapeutic actions by a cardiac transcriptome weighted gene coexpression network analysis, was confirmed using AAV5-hS100A1 therapy in a post-MI mouse model, as measured by RT-PCR and echocardiography. Conclusion: Providing the clinically relevant proof-of-concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility as well as low pre-existing immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease as chronic heart failure, using therapeutic genetic effectors, such as hS100A1 or others.

Dataset Information

Bone Morphogenetic Protein 9 Protects against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics

Publications

Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics.

Similar Datasets

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