Olmesartan attenuates pressure-overload- or post-infarction-induced cardiac remodeling in mice

Figures

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  Figure 1. Antihypertrophic effect of temocapril, olmesartan or their combination (A) Representative pictures of whole heart at 1 week after TAC or sham operation with or without drug-treatment. (B) Heart weight to body weight ratio (HW/BW) and (C) lung weight to body weight ratio (LW/BW) at 1 week after TAC, treatment with or without temocapril (Tem), olmesartan (Olm) or their combination. *P < 0.05 vs. sham group, #P < 0.05 vs. TAC group in panel B and C. (D) Representative pictures of whole heart and lung at 4 weeks after TAC or sham operation with or without drug-treatment. (E) HW/BW ratio and (F) LW/BW ratio at 4 weeks after TAC, treatment with or without temocapril, olmesartan or their combination. (G) Left ventricular systolic function, quantified by left ventricle fractional shortening (LVFS) at 4 weeks after TAC in five groups. *P < 0.05 vs. sham group, #P < 0.05 vs. TAC group in panel E, F and G.

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  Figure 2. Gene expression patterns in response to TAC and drug treatment (A) A time course of global gene expression at 1 and 4 weeks’ time points. As shown by the red lines, expression pattern in response to TAC at 1 and 4 weeks is similar. (B) The high expression genes with more than 2 folds upregulation in average difference relative to control signal in TAC group demonstrated a tendency of downregulation in sham and 3 drug-treated groups. (C) Among the upregulated 109 genes in TAC relative to sham, 8 co-regulated genes was identified. (D–I) Validation of the microarray results by using quantitative PCR. BNP: natriuretic peptide precursor type B, EMP1: epithelial membrane protein 1, CARP: cardiac ankyrin repeat protein mRNA. Combin or combination: combination with temocapril (Tem) and olmesartan (Olm). *P < 0.05 vs, **P < 0.01. TAC group in panel D–I.

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  Figure 3. Confirmation of ankrd1 and periostin involving in myocyte hypertrophy or post-MI cardiac remodeling by using approaches of gain and loss of function (A) Western blotting confirmation of ankrd1 overexpression with adenovirus carrying ankrd1 plasmid (Ad-Ankrd1) in neonatal rat cardiomyocytes. (B) Representative pictures showing cross area of cardiomyocytes in response to angiotensin II (Ang II) stimulation in the presence/absence of ankrd1 overexpression. Scale bar = 50 µm. (C) Ankrd1 overexpression enhanced Ang II-induced increase of cardiomyocyte area. *P < 0.05 vs. control group, #P < 0.05 vs. Ang II alone group, experiments were repeated for 3 times. (D) Representative pictures of cardiac cross section with Masson staining 4 weeks after myocardial infarction (MI). Scale bar = 2 mm. (E) Periostin knockout (KO) attenuated post-MI fibrosis. *P < 0.05 vs. sham group, #P < 0.05 vs. MI alone group, n = 6 in each group. WT, wildtype; LVC, left ventricular circumference.

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  Figure 4. Treatment of olmesartan attenuates left ventricular dysfunction at 4 weeks after MI (A) ST segment elevation in electrocardiogram monitoring showed an MI model was successful. (B) TTC staining in mice 24 h after MI showed the infarcted area (fibrotic length) was similar in olmesartan (Olm)-treated and untreated MI groups. The scale bar is 5 mm. (C) Representative images of M-mode echocardiography. (D) Results of echocardiographic left ventricular dimensions. LVEDd, left ventricular end-diastolic diameter; LVESd, left ventricular end-systolic diameter. (E) Results of echocardiographic left ventricular wall thickness. LVAWd: left ventricular anterior wall thickness; LVPWd: left ventricular posterior wall thickness. (F) Results of echocardiographic left ventricular fractional shortening (LVFS). *P < 0.05 vs. their corresponding sham group, #P < 0.05 vs. MI group in panel D–F.

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  Figure 5. Olmesartan (Olm) treatment improves left ventricular hemodynamic at 4 weeks after myocardial infarction (MI) (A) Examples of left ventricular pressure curve recording. (B) Left ventricular systolic pressure (LVSP). (C) Maximum rates of left ventricular rising and descending (dp/dt max, dp/dt min). (D) Left ventricular contractility. (E) Left ventricular end-diastolic pressure (LVEDP). (F) The exponential time constant of left ventricular relaxation (tau). *P < 0.05 vs. sham group, #P < 0.05 vs. MI group in panel D–F.

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  Figure 6. Olmesartan alleviates post-infarction remodeling at 4 weeks (A) Heart weight/body weight (HW/BW) at 4 weeks after MI with or without olmesartan (Olm) treatment. (B) Lung weight/BW (LW/BW) increased in mice subjected to MI and decreased by olmesartan treatment. *P < 0.05 vs. sham group, #P < 0.05 vs. MI group. (C) Masson’s trichrome staining of hearts obtained at 4 weeks after MI. The lower panels show magnifications of the regions indicated by black boxes in the upper panels. The scale bar is 1 mm in the upper panel and 100 μm in the lower panel. (D) Quantitation of old myocardial infarction area (Masson’s trichrome positive staining length of LV/LV circle). * P < 0.05 vs. MI group. IA: infarct area).

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  Figure 7. Periostin expression in olmesartan (Olm)-treated mice at 4 weeks after myocardial infarction (MI) (A) Hematoxylin-eosin (HE) (top), immunohistochemistry (IHC) of periostin (middle) staining of mouse hearts at 4 weeks after MI. The lower panels show magnifications of the region indicated by black arrows in the upper panels. The scale bar is 200 μm in the top and middle panels, and 100 μm in the lower panel. (B) Semi-quantitative analysis of periostin staining in each group. *P < 0.05 vs. their corresponding sham group, #P < 0.05 vs. MI group.

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  Figure 8. Effect of periostin knockout on expression of GSK3β and cyclin D1 at 7 days after myocardial infarction (A) Representative examples of western blotting of myocardial GSK3β and cyclin D1. (B) Semi-quantitation of myocardial GSK3β and cyclin D1. *P < 0.05 vs. their corresponding sham group, #P < 0.05 vs. MI group, n = 5 in each group.