Cholecystokinin octapeptide reduces myocardial fibrosis and improves cardiac remodeling in post myocardial infarction rats

ABSTRACT: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and has beneficial effects against hypertension and myocardial ischemia/reperfusion injury. Little is known about the role of apelin in the homing of vascular progenitor cells (PCs) and cardiac remodeling post-myocardial infarction (MI). The present study investigates whether apelin affects PCs homing to the infarcted myocardium thereby mediating cardiac remodeling post-MI. Mice were infarcted by coronary artery ligation and apelin-13 (1 mg/kg.d) was injected for three days prior to MI and for either 24 hours or 14 days post MI. Homing of vascular progenitor cell (CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and CD133 + /CXCR4 + ) into the ischemic area were examined at 24 hours and 14 days post-MI. Myocardial Akt, eNOS, VEGF, Jagged1, Notch3, SDF-1α and CXCR4 expression were assessed. Functional analyses were performed at day 14 after MI. Mice receiving apelin-13 treatment demonstrated upregulation of SDF-1α/CXCR4 expression and dramatically increased the number of CD133 + /c-kit + /Sca1 + , CD133 + /SDF-1α + and c-kit + /CXCR4 + cells in the infarcted hearts. Apelin-13 also significantly increased Akt and eNOS phosphorylation and upregulated VEGF, Jagged1, Notch3 expression in the ischemic hearts. This was accompanied by a significant reduction of myocardial apoptosis. Further, treatment with apelin-13 promoted myocardial angiogenesis, attenuated cardiac fibrosis and hypertrophy together with a significant improvement of cardiac function at 14 days post-MI mice. Apelin-13 increases angiogenesis and improves cardiac remodeling by a mechanism involving upregulation of SDF-1α/CXCR4 and homing of vascular progenitor cells.

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Abstract 358: Myeloid-specific Il-4 Receptor α Knockout Alters Cardiac Remodeling Post-myocardial Infarction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.358 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jianrui Song ◽

Thomas Vigil ◽

Yutein Chung ◽

Ryan Frieler ◽

Sascha Goonewardena ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Cardiac Remodeling ◽

Post Myocardial Infarction ◽

Critical Determinant ◽

Tetrazolium Chloride ◽

Alternatively Activated Macrophages ◽

Inflammatory Reactions ◽

Infarct Healing ◽

Adverse Remodeling

Introduction: Cardiac remodeling post myocardial infarction (MI) can be a critical determinant of outcome for patients with MI. Well-contained inflammation results in successful infarct healing while excessive inflammation cause adverse remodeling which leads to heart failure. Macrophages are important participants in inflammation, helping resolve pro-inflammatory reactions and performing reparative processes. Reprogramming macrophages towards a resolving and reparative phenotype is a potential therapeutic approach. We hypothesized that IL4/IL13-induced, alternatively activated macrophages (M2) have an important role in cardiac remodeling post-MI, and we tested this hypothesis in a mouse model of MI using myeloid-specific IL4 receptor α knockout mice (MyIL4RaKO). Methods: MyIL4RaKO mice were generated using IL4Ra flox/flox ;LysM-Cre. MI was induced by ligating the left anterior descending coronary artery. Hearts were cut into 1mm sections, and then stained by tetrazolium chloride for infarct size measurement. Evenly spaced radians were taken through the infarct with the center of left ventricle in 5μm heart sections, and the average infarct thickness was calculated. qPCR was used to determine gene expression. Echocardiography was performed at baseline and 3 weeks post MI. Results: Initial infarct size was not affected by IL4Ra knockout but at 1-week post MI, infarct size of MyIL4RaKO mice (16.54 ± 2.433, n=11) was shown significantly smaller than that of FC mice (24.96 ± 2.005, n=15) showing changes in remodeling (p= 0.0129). Changes in remodeling continued and at 3-week post MI, infarct thickness of MyIL4RaKO mice (0.2171 ± 0.01053, n=6) was significantly increased, compared with that of FC mice (0.3508 ± 0.03629, n=8, p= 0.0094). These changes were accompanied by MyIL4RaKO mice also showed lower level of fibrosis markers: Col1A1 and Plod2. A significantly lower ejection fraction was observed in MyIL4RaKO mice (25.46 ± 3.749, n=5) compared with FC mice (37.90 ± 2.309, n=5) at 3 weeks (p= 0.0223). Conclusions: Myeloid-specific IL4Ra knockout results in alteration of remodeling, altered fibrosis and decreased cardiac function post MI, although the cardiac hypertrophy did not show significant change.

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Implications of the transcription factor WT1 linked to the pathologic cardiac remodeling post-myocardial infarction

Clínica e Investigación en Arteriosclerosis (English Edition) ◽

10.1016/j.artere.2019.05.002 ◽

2019 ◽

Vol 31 (3) ◽

pp. 121-127

Author(s):

Raúl Lelio Sanz ◽

Luciana Mazzei ◽

Walter Manucha

Keyword(s):

Myocardial Infarction ◽

Transcription Factor ◽

Cardiac Remodeling ◽

Post Myocardial Infarction

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Adapting extracellular matrix proteomics for clinical studies on cardiac remodeling post-myocardial infarction

Clinical Proteomics ◽

10.1186/s12014-016-9120-2 ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 19

Author(s):

Merry L. Lindsey ◽

Michael E. Hall ◽

Romain Harmancey ◽

Yonggang Ma

Keyword(s):

Myocardial Infarction ◽

Extracellular Matrix ◽

Cardiac Remodeling ◽

Clinical Studies ◽

Post Myocardial Infarction

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CD8+T-cells negatively regulate inflammation post-myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00112.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. H581-H596 ◽

Cited By ~ 14

Author(s):

Daria V. Ilatovskaya ◽

Cooper Pitts ◽

Joshua Clayton ◽

Mark Domondon ◽

Miguel Troncoso ◽

...

Keyword(s):

Myocardial Infarction ◽

T Cells ◽

Cardiac Remodeling ◽

Scar Formation ◽

Post Myocardial Infarction ◽

Cardiac Rupture ◽

Necrotic Tissue ◽

Cardiac Physiology ◽

Wild Type ◽

Delayed Removal

The adaptive immune response is key for cardiac wound healing post-myocardial infarction (MI) despite low T-cell numbers. We hypothesized that CD8+T-cells regulate the inflammatory response, leading to decreased survival and cardiac function post-MI. We performed permanent occlusion of the left anterior descending coronary artery on C57BL/6J and CD8atm1makmice (deficient in functional CD8+T-cells). CD8atm1makmice had increased survival at 7 days post-MI compared with that of the wild-type (WT) and improved cardiac physiology at day 7 post-MI. Despite having less mortality, 100% of the CD8atm1makgroup died because of cardiac rupture compared with only 33% of the WT. Picrosirius red staining and collagen immunoblotting indicated an acceleration of fibrosis in the infarct area as well as remote area in the CD8atm1makmice; however, this increase was due to elevated soluble collagen implicating poor scar formation. Plasma and tissue inflammation were exacerbated as indicated by higher levels of Cxcl1, Ccl11, matrix metalloproteinase (MMP)-2, and MMP-9. Immunohistochemistry and flow cytometry indicated that the CD8atm1makgroup had augmented numbers of neutrophils and macrophages at post-MI day 3 and increased mast cell markers at post-MI day 7. Cleavage of tyrosine-protein kinase MER was increased in the CD8atm1makmice, resulting in delayed removal of necrotic tissue. In conclusion, despite having improved cardiac physiology and overall survival, CD8atm1makmice had increased innate inflammation and poor scar formation, leading to higher incidence of cardiac rupture. Our data suggest that the role of CD8+T-cells in post-MI recovery may be both beneficial and detrimental to cardiac remodeling and is mediated via a cell-specific mechanism.NEW & NOTEWORTHY We identified new mechanisms implicating CD8+T-cells as regulators of the post-myocardial infarction (MI) wound healing process. Mice without functional CD8+T-cells had improved cardiac physiology and less mortality 7 days post MI compared with wild-type animals. Despite having better overall survival, animals lacking functional CD8+T-cells had delayed removal of necrotic tissue, leading to poor scar formation and increased cardiac rupture, suggesting that CD8+T-cells play a dual role in the cardiac remodeling process.

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