Project description:Background: Postmenopausal women have higher risks of myocardial infarction (MI) and subsequent cardiac dysfunction. Exercise is widely recognized to protect the cardiovascular system, but its molecular mechanisms in postmenopausal MI remain not fully understood. This study explored the effects and mechanism of swimming exercise against cardiac dysfunction in ovariectomized (OVX) mice post-MI. Methods: OVX mice were subjected to a 3-week swimming training before MI induction via permanent ligation of left anterior descending artery. Cardiac systolic function was evaluated by echocardiography. Masson, HE, WGA staining, RT-qPCR, and Western blotting were combined to detect the extent of cardiomyocyte hypertrophy, myocardial fibrosis, and apoptosis. To explore the key exercise-effectors, we detected microRNAs (miR-21, miR-146a, miR-155) in serum samples of elderly post-MI women subsequent to exercise rehabilitation training. miR-21 expression was further investigated in heart sample of OVX plus MI mice. The role of miR-21 in vivo was elucidated through miR-21 knockout mice model and AAV9-mediated miR-21 overexpression mice model. The function of miR-21 in vitro were evaluated in cardiac fibroblasts isolated from OVX mice and treated with TGF-β to induce its activation. miR-21 targets were revealed by microarray analysis and verified by luciferase reporter and functional rescue assays. Results: Swimming significantly improved cardiac function in OVX mice post-MI, alleviated cardiomyocyte hypertrophy, reduced myocardial fibrosis, and inhibited apoptosis. miR-21 expression was downregulated by exercise training both in heart of OVX mice post-MI and in serum of elderly women after MI. miR-21 knockout mimicked swimming’s cardioprotective effects towards OVX mice post-MI, while miR-21 overexpression abolished these effects. The overexpression of miR-21 promoted the TGF-β-induced differentiation of cardiac fibroblasts into myofibroblasts and their proliferation, whereas its inhibition blocked TGF-β’s pro-fibrotic role. Microarray analysis and luciferase assays identified Sox7 as a direct miR-21 target, and Sox7 knockdown reversed anti-fibrotic effect of inhibiting miR-21. Conclusion: Swimming protects against post-MI cardiac dysfunction in OVX mice by downregulating myocardial miR-21, thereby upregulating its target gene Sox7 and inhibiting cardiac fibroblast activation. miR-21 and its downstream target Sox7 contributes to cardioprotective effects of swimming, offering a potential target for postmenopausal MI treatment.

Project description:BACKGROUND: Myocardial infarction (MI), one of the leading causes of mortality worldwide, remains a clinical challenge due to limitations in current therapeutic strategies. The cardiac vascular network, as the fundamental architecture sustaining myocardial function, delivers oxygen and nutrients with high precision to the heart tissue. However, the dynamic regulatory mechanisms governing this network post-MI remain incompletely elucidated. Notably, the pivotal role of cardiac endothelial cells in the pathophysiological progression of MI calls for further comprehensive investigation.METHODS: We examined alterations in Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein expression in the myocardium of MI-afflicted mice and human MI heart tissues. Utilizing genetically engineered mouse models in combination with diverse cellular and molecular biology techniques, we systematically dissected the functional role of SCUBE3 in MI and its underlying mechanisms in cardiac endothelial cell metabolism.RESULTS: Proteomic profiling of serum samples from MI patients demonstrated a significant elevation in SCUBE3 protein levels. Immunohistochemical assessment revealed markedly increased SCUBE3 expression localized predominantly within fibroblasts in the infarct zone of cardiac tissues from MI patients. Consistently, in a murine MI model, SCUBE3 expression was also upregulated and primarily distributed in fibroblasts within the infarcted myocardial regions. Employing inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we observed that SCUBE3 overexpression robustly enhanced post-MI angiogenesis, improved microcirculatory network integrity, and attenuated myocardial injury. In contrast, SCUBE3 ablation exacerbated infarct-induced cardiac damage. Subsequent protein tracking and mass spectrometry analyses demonstrated that SCUBE3 selectively binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, thereby mediating downstream biological effects. Transcriptomic sequencing revealed that SCUBE3 significantly upregulates fatty acid metabolism–related pathways. Live-cell dynamic analysis further confirmed that SCUBE3 promotes fatty acid uptake and enhances the metabolic activity of endothelial cells. Metabolomic profiling indicated that SCUBE3 facilitates the conversion of unsaturated fatty acids into phosphosugars and nucleotides, supplying essential substrates and energy to support endothelial cell proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible VEGFR1 knockout completely abrogated SCUBE3-driven fatty acid metabolism and its associated cardioprotective effects. Moreover, beyond its role in angiogenesis SCUBE3 also markedly enhances cardiomyocyte regenerative capacity, highlighting its potential as a novel therapeutic target for myocardial repair.

Project description:BACKGROUND: Myocardial infarction (MI), one of the leading causes of mortality worldwide, remains a clinical challenge due to limitations in current therapeutic strategies. The cardiac vascular network, as the fundamental architecture sustaining myocardial function, delivers oxygen and nutrients with high precision to the heart tissue. However, the dynamic regulatory mechanisms governing this network post-MI remain incompletely elucidated. Notably, the pivotal role of cardiac endothelial cells in the pathophysiological progression of MI calls for further comprehensive investigation.METHODS: We examined alterations in Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein expression in the myocardium of MI-afflicted mice and human MI heart tissues. Utilizing genetically engineered mouse models in combination with diverse cellular and molecular biology techniques, we systematically dissected the functional role of SCUBE3 in MI and its underlying mechanisms in cardiac endothelial cell metabolism.RESULTS: Proteomic profiling of serum samples from MI patients demonstrated a significant elevation in SCUBE3 protein levels. Immunohistochemical assessment revealed markedly increased SCUBE3 expression localized predominantly within fibroblasts in the infarct zone of cardiac tissues from MI patients. Consistently, in a murine MI model, SCUBE3 expression was also upregulated and primarily distributed in fibroblasts within the infarcted myocardial regions. Employing inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we observed that SCUBE3 overexpression robustly enhanced post-MI angiogenesis, improved microcirculatory network integrity, and attenuated myocardial injury. In contrast, SCUBE3 ablation exacerbated infarct-induced cardiac damage. Subsequent protein tracking and mass spectrometry analyses demonstrated that SCUBE3 selectively binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, thereby mediating downstream biological effects. Transcriptomic sequencing revealed that SCUBE3 significantly upregulates fatty acid metabolism–related pathways. Live-cell dynamic analysis further confirmed that SCUBE3 promotes fatty acid uptake and enhances the metabolic activity of endothelial cells. Metabolomic profiling indicated that SCUBE3 facilitates the conversion of unsaturated fatty acids into phosphosugars and nucleotides, supplying essential substrates and energy to support endothelial cell proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible VEGFR1 knockout completely abrogated SCUBE3-driven fatty acid metabolism and its associated cardioprotective effects. Moreover, beyond its role in angiogenesis SCUBE3 also markedly enhances cardiomyocyte regenerative capacity, highlighting its potential as a novel therapeutic target for myocardial repair. Conclusions: Our findings establish that fibroblast-derived SCUBE3 interacts with VEGFR1 on endothelial cells to promote fatty acid metabolism, thereby providing energy substrates necessary for endothelial proliferation. This study elucidates the critical function of the SCUBE3–VEGFR1 signaling axis in post-MI vascular regeneration through metabolic regulation, presenting a promising avenue for therapeutic intervention in cardiac repair.

Dataset Information

Cardiomyocyte-Derived HSPB1 Regulates TGF-β1 Maturation and Inhibits Endothelial-to-Mesenchymal Transition in Myocardial Fibrosis after Infarction

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Cardiomyocyte-derived HSPB1 regulates TGF-β1 maturation and inhibits endothelial-to-mesenchymal transition in myocardial fibrosis.

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