Effect of simvastatin on collagen I deposition in non-infarcted myocardium: role of NF-κB and osteopontin

The novel biological effect of statins in alleviating myocardium fibrosis following infarction has been increasingly recognized, yet the underlying mechanisms are not fully understood. The purpose of this study was to characterize the effect of simvastatin on myocardial fibrosis and collagen I deposition in the non-infarcted region after myocardial infarction (MI) and to identify the role of NF-κB and osteopontin in simvastatin-mediated inhibition of post-MI collagen over-expression. A rat model of MI was generated by ligating the left anterior descending coronary artery. The rats surviving the MI operation were randomly divided into the following 3 groups: myocardial infarction (MI, vehicle), simvastatin (Sim, 30 mg·kg–1·day–1), and pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB, 100 mg·kg–1·day–1). Four weeks after MI, cardiac function, mRNAs, and protein expression in non-infarcted myocardium were analyzed. Myocardial fibrosis and collagen I over-expression were observed following MI, accompanied by an increase of NF-κB and osteopontin. Simvastatin improved post-MI left ventricular dysfunction and ameliorated post-MI associated changes to several cardiac parameters, including the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure development (+dP/dtmax), and the maximal rate of pressure decline (–dP/dtmax). Concurrently, simvastatin significantly suppressed the over-expression of NF-κB, osteopontin, and collagen I in the non-infarcted region following MI. Inhibition of NF-κB by PDTC also reduced osteopontin over-expression and excessive collagen I production and improved the above functional myocardial parameters. These results show that post-MI myocardial fibrosis and collagen I over-expression in the non-infarcted region is associated with activation of NF-κB and osteopontin up-regulation. The anti-fibrotic effect of simvastatin following MI is associated with the attenuation of the expression of osteopontin and NF-κB. The inhibition of NF-κB activation could be the process upstream of osteopontin suppression in the simvastatin-mediated effect.

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Abstract 208: The Interaction of Neutrophils and Interferon Gamma Promotes Post-infarct Survival in a Mouse Model of Myocardial Infarction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.208 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Stefanie Finger ◽

Maike Knorr ◽

Sabine Kossmann ◽

Tanja Schoenfelder ◽

Susanne Karbach ◽

...

Keyword(s):

Myocardial Infarction ◽

Mrna Expression ◽

Healing Process ◽

Cardiac Injury ◽

Flow Cytometric Analysis ◽

Left Ventricular ◽

Infarcted Myocardium ◽

Inflammatory Monocytes ◽

Initial Injury

Background: Myelomonocytic cells are involved in both the initial injury phase and the healing process of myocardial infarction (MI). However, the exact interaction of inflammatory myeloid cells and prominent cytokines remains only partly understood. Objective: The goal of the study was to investigate the either cardioprotective or in part adverse role of lysozyme M positive (LysM+) and granulocyte-receptor 1 positive (Gr-1+) immune cells on cardiac injury and healing in a murine model of MI. Methods and results: MI was induced in 8 to 12 week-old male mice (C57BL/6 background) by ligation of the left anterior descending (LAD) coronary artery. Compared to LysMCre controls, LysM+ cell depleted LysMiDTR transgenic mice (depletion 3d prior MI by diphtheria toxin application, 25 ng/g body weight) showed a decreased influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1d post MI (measured by flow cytometric analysis). Additionally cardiac mRNA expression levels of inflammatory cytokines like INFγ and TNFα were decreased 7d post MI. To more specifically assess the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality early after MI as well as a decrease in INFγ mRNA expression 1d and 7d post MI. MCP-1 (CCL2) and CCR2 mRNA were reduced 3d after MI according to decreased amount of CD11b+/Ly6G-/Ly6Chigh inflammatory monocytes in the infarcted myocardium of anti-Gr-1 treated mice. LAD ligated INFγ-/- mice displayed a significantly reduced survival, worsening of left ventricular function and an impaired inflammatory cell infiltration compared to C57BL/6 controls. Conclusion: We provide evidence that neutrophils and INFγ play an essential role in survival and cardiac remodeling following MI. Our data indicate that neutrophils are required for monocyte chemotaxis. We conclude, that strategies to combat the inflammatory injury in MI must consider a potentially beneficial effect of early neutrophil influx into infarcted myocardium.

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Faculty Opinions recommendation of Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1081843.534768 ◽

2007 ◽

Author(s):

Fabio Recchia

Keyword(s):

Myocardial Infarction ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Critical Role ◽

Left Ventricular ◽

Oxidase Subunit

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Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

Journal of Cardiac Failure ◽

10.1016/s1071-9164(99)91277-0 ◽

1999 ◽

Vol 5 (3) ◽

pp. 79

Author(s):

Shintaro Kinugawa ◽

Hiroyuki Tsutsui ◽

Tomomi Ide ◽

Hideo Ustumi ◽

Nobuhiro Suematsu ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular

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Role of Left Ventricular Dyssynchrony in Predicting Remodeling after ST Elevation Myocardial Infarction

Echocardiography ◽

10.1111/j.1540-8175.2011.01574.x ◽

2011 ◽

Vol 29 (2) ◽

pp. 165-172 ◽

Cited By ~ 9

Author(s):

Burak Turan ◽

Fatih Yilmaz ◽

Tansu Karaahmet ◽

Kursat Tigen ◽

Bulent Mutlu ◽

...

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

St Elevation Myocardial Infarction ◽

Left Ventricular Dyssynchrony ◽

Ventricular Dyssynchrony ◽

St Elevation

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Novel role of platelet reactivity in adverse left ventricular remodelling after ST-segment elevation myocardial infarction: The REMODELING Trial

Thrombosis and Haemostasis ◽

10.1160/th16-10-0744 ◽

2017 ◽

Vol 117 (05) ◽

pp. 911-922 ◽

Cited By ~ 4

Author(s):

Yongwhi Park ◽

Udaya Tantry ◽

Jin-Sin Koh ◽

Jong-Hwa Ahn ◽

Min Kang ◽

...

Keyword(s):

Myocardial Infarction ◽

Platelet Reactivity ◽

Left Ventricular ◽

Ventricular Remodelling ◽

Left Ventricular Remodelling ◽

St Segment Elevation ◽

Segment Elevation Myocardial Infarction ◽

St Segment ◽

Hs Crp

SummaryThe role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20 % increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0 %). According to PRU quartile, LVR rate was 10.8 % in the first, 23.1 % in the second, 27.0 % in the third, and 35.1 % in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95 % confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

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