ABSTRACT
The Sarcolemmal Membrane Associated Protein 3 (SLMAP3) is a tail-anchored membrane protein, which is ubiquitously expressed in tissues including myocardium. It is a component of subcellular membranes and the centrosome, and it appears to serve distinct roles in cell growth and membrane biology. In addition, mutations in SLMAP have been linked to Brugada syndrome, which leads to cardiac dysfunction and death. Here, we have examined the effects of different levels of SLMAP3 on postnatal heart function, pre and post myocardial infarction (MI).Transgenic (TG) mice with a cardiac specific expression of SLMAP3 isoform were generated and assessed with echocardiography to measure function, immunohistochemistry for histology, TUNEL assay for apoptosis, Masson’s trichrome staining for fibrosis, and Western blots for protein expression.
Baseline echocardiography of 8 weeks old TG mice showed a normal cardiac function that was expressed in ejection fraction percent (%EF=66%±7.42), which was similar to those of wild type mice (%EF=67%±9.36), p<0.05, n=20-25 (in each group). MI was induced by permanent ligation of left anterior descending (LAD) artery in 9 week old WT & TG mice, while sham was the control. No death was recorded in SLMAP3 TG mice up to one year post MI, whereas 70% of WT mice had deceased, p<0.01, n=17-18 (in each group). Cardiac function was assessed by echocardiography (at 4 week post MI) showed a partially restored ejection fraction percent (%EF~49.2%±17.02) in SLMAP3 TG mice post MI compared to (%EF~36.4%±15.25) in WT mice post MI, p<0.05, n=15-16 (in each group). Furthermore, infarct size (IS) as well as collagen area (CA) post MI were significantly attenuated (IS~43%±8.82, CA~35%±5.15) in SLMAP3 TG myocardium in comparison to WT (IS~53%±9.30, CA~47%±7.36), p<0.05, n=20- 22 (each group). Moreover, expression of the heart failure biomarker galectin3 was markedly
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attenuated (1.8±0.20) in SLMAP3 TG hearts post MI compared to (3.2±0.35) in WT, p<0.01, n=4-5 (in each group). The apoptotic index in SLMAP3 TG myocardium assessed by TUNEL was markedly decreased (77±11.48) in comparison to WT (112±15.32), p<0.05, (n=20-22 in each group). Further, expression of proapoptotic proteins (Caspase3 and Bax) was significantly attenuated in SLMAP3 TG (p<0.05, n=4-5 in each group) while the expression of the prosurvival proteins (Bcl2 and caveolin3) was significantly upregulated (p<0.05, n=4-5 (in each group) in post MI. These data indicate that increased SLMAP3 levels serve to protect myocardium post MI through mechanisms which promote cell survival and limit cardiac fibrosis. Strategies to increase SLMAP3 level in myocardium may provide new therapeutic options in the treatment of heart failure.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/35713 |
| Date | January 2017 |
| Creators | Lefnaier, Wafa |
| Contributors | Tuana, Balwant |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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