The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Abstract

Aim: Rasagiline mesylate (N-propargyl-1 (R)-aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase-B with cardioprotective and anti-apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery.

Methods and results: RG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end-systolic and diastolic dimensions and preserved fractional shortening in RG-treated compared with normal saline group at 28 days post-MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non-infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress.

Conclusions: Our study demonstrates a positive effect of RG in the post-MI period with a significant attenuation in cardiac remodelling.

Keywords: Apoptosis; Cardiac remodelling; Fibrosis; Myocardial infarction; Rasagiline mesylate.

Figure 1

Rasagiline mesylate (RG) improves cardiac dysfunction at 14 and 28 days post‐MI induction, without altering infarct size. (A) Representative 2D targeted M‐mode images from the short axis view. (B) RG diminished the decrease in FS compared with N/S‐treated group at 14 and 28 days (P < 0.0001). (C) Quantification diagram of infarct/risk area ratio (I/R %) and (D) Risk/all area ratio (%) as internal control of the method. *P < 0.001, **P < 0.0001 vs. Sham and †P < 0.001, ††P < 0.0001 vs. RG.

Figure 2

Interstitial fibrosis was evaluated by immunofluorescence staining of BZ tissue sections (green = desmin, red = collagen‐αI, bar = 25 μm). (A) Sham group. (B) RG showed decreased interstitial fibrosis compared with N/S group (C). (D) Quantification diagram of collagen score between groups (P < 0.05 vs. N/S). (Ε) Fibrosis assay analysis showed that in the BZ, RG treatment decreased myocardial hydroxyproline concentration compared with N/S group (P < 0.05, n = 5). (F) Quantification diagrams showing variations in mRNA relative expression of TGF‐β1, TIMP‐2, and collagen type I genes in the BZ and (G) RR between groups (n = 5). Values are mean ± SE, *P < 0.05, **P < 0.01 vs. N/S.

Figure 3

The relative protein expression levels of Caspase 3, Bax, and Bcl2 were estimated by Western blot in RR (A) and BZ (B). (C) Representative western blot images are depicted. Cleaved Caspase 3 protein levels were diminished in the RR of the RG compared with N/S group (P < 0.0001, n = 5). (D) TUNEL quantification showed a significant reduction of apoptotic myocytes by 65% in the BZ of RG compared with N/S group (P < 0.05, n = 5). Values in mean ± SE, *P < 0.05, **P < 0.0001 vs. N/S. Representative images of BZ tissue sections from sham (E), RG (F), and N/S (G) group were stained for TUNEL nuclei (red), connexin‐43 (green), and DAPI (blue). Bar 50 μm.

Figure 4

(A) MDA levels were estimated in tissue extracts from BZ and RR. RG diminished MDA levels in BZ compared with N/S group (P < 0.001, n = 4). (B) Western blot analysis showed variations in small ubiquitin‐related modifier‐1 relative protein expression levels from RG and N/S group in the BZ and RR (n = 4). Values in mean ± SE, *P < 0.05, **P < 0.001 vs. N/S.