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Introduction:We have examined the process of myocardial infarction in SR-BI KO/ApoeR61h/h mice which is a valuable, high-fat-diet (HFD) induced myocardial infarction model mice (Plos One. 2013, J Atheroscler Thromb. 2019). We identified the dynamics of T-cell subsets in SR-BI KO/ApoeR61h/h mice during myocardial infarction and further performed a therapeutic intervention with probucol, antihyperlipidemic drug and a potent antioxidant agent.Hypothesis:Probucol might decrease the specific CD4+T-cell subset such as Th1 and Th17 and increase Treg during myocardial infarction.Methods:8-to13- week-old SR-BI KO/ApoeR61h/h mice were fed HFD for 7 days to induce myocardial infarction. After that, the mice were fed a chow diet with or without probucol. The dynamics of T-cell subset was investigated by flow cytometric and histological analysis.Results:After HFD, troponin I increased and EF decreased gradually in SR-BI KO/ApoeR61h/h mice. The dynamics of T-cell subsets in blood and spleen were analyzed by flow cytometry. Number of CD4+ and CD8+ T-cells peaked on day 7. In CD4+ T-cell subsets in spleen, the number of Th1 and Th17 increased. Histological analyses showed that CD4+, CD8+T-cell and Treg infiltration was detected in the infarcted myocardium. Interestingly, the distribution was different. The number of Th1 significantly decreased by 90% on day 1 week after the administration of probucol (p<0.05). CD4+ T-cells control the infiltration and the differentiation of recruited pro-inflammatory monocytes. Infiltration of macrophage in infarcted myocardium was reduced by 90% with probucol treatment compared to non-treatment (p=0.0133). Cardiac fibrosis was also significantly reduced by 85% with probucol treatment compared to non-treatment (P<0.05). The survival curve of the probucol-treated group was improved significantly as compared with the non-treatment group (survival rate: 70% vs 50%, respectively, p<0.001)Conclusions:CD4+T-cells are expanded during myocardial infarction with Th1 and Th17 predominance in SR-BI KO/ApoeR61h/hmice. Therapeutic intervention with probucol suggests that the analyses of T-cell subsets by using SR-BI KO/ApoeR61h/hmice could possibly lead to a new anti-inflammatory therapy for myocardial infarction.

Purpose:Ventricular fibrosis is promoted by many effectors that chronically activate phospholipase D (PLD), and induces cardiac dysfunction and heart failure in cardiovascular diseases. Since ethanolamine is a product of PLD, we hypothesized that an administration of an analogue of ethanolamine, N-methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and prevents organ dysfunction.Methods and Results:In human fibroblasts 1-butanol inhibited collagen synthesis and enhanced collagenase production, but iso-butanol did not. These indicate crucial roles of PLD in collagen synthesis and degradation. In fibroblasts, MEA dose-dependently decreased PLD activity, inhibited collagen synthesis and enhanced collagenase production. In a hypertensive heart failure (HHF) model using Dahl-Iwai salt-sensitive rats, PLD activity increased with progressive ventricular fibrosis, leading to myocardial stiffening and overt heart failure. Long-term administration of MEA did not significantly decrease blood pressure, however, decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to prevention of myocardial stiffening and hemodynamic deterioration. MEA also attenuated ventricular hypertrophy, another detrimental structural alteration.Conclusion:MEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of fibrosis pathway even without a release from mechanical stress.