Introduction: Myocardial Infarction (MI) is the leading cause of premature death worldwide. During MI-induced ischemia, the release of heat shock proteins (HSPs), a classic damage-associated molecular pattern (DAMP), by severely injured cells leads to prolonged inflammation through their activation of innate pattern recognition receptors, fibrosis, and subsequent contractile dysfunction. The regulation of HSPs is orchestrated by its master transcription factor, Heat Shock Factor 1 (HSF1). However, it is unknown if HSF1 is a potential integrated functional target to improve MI outcomes. We addressed this question by asking if the coordinated modulation of HSPs via genetic deletion of Hsf1 can be beneficial in MI.
Hypothesis: We hypothesized that genetic deletion of Hsf1 can lead to improved survival and left ventricle (LV) remodeling through reduction of pro-inflammatory pathway activation in a murine model of MI-induced coronary artery ligation.
Methods and Results: Eleven to thirteen-week-old male Hsf1-/- mice and Hsf1+/+ littermate controls were subjected to MI by left anterior descending (LAD) coronary artery ligation or sham operation. Hsf1-/- mice subjected to induced-MI had a significant higher survival rate (74%) at 28 days than WT mice post-MI in the same time frame (34%, p<0.001). Echocardiography at 3, 7, and 28 days post-MI; however, did not identify any difference in LV function between Hsf1+/+ and Hsf1-/- mice. Masson Trichrome and Picro Sirius Red staining of heart tissue sections following 7 days of sham or MI-operation indicated that MI-operated Hsf1-/- hearts had a significant smaller infarct size than Hsf1+/+ hearts at 19% compared to 32% (p<0.05), respectively; and less collagen deposition when compared to WT littermates. Cardiac expression of heat shock proteins was significantly lowered in the Hsf1-/- hearts compared to Hsf1+/+ hearts following 3 and 7 days of MI. However, no significant difference was observed in number of immune cells, cardiac gene expression of pro-inflammatory cytokines and chemokines, cardiac protein expression of NF-κB and MAPK-ERK1/2 signaling proteins, and serum IL-6 concentration between Hsf1+/+ and Hsf1-/- mice 3 days post-MI. Following 7 days of MI, there is a significant increase in the gene expression of pro-inflammatory cytokines, such as Il1b, and chemokines, such as Ccl2, in Hsf1-/- hearts than Hsf1+/+ hearts.
Conclusion & Future Directions: Overall, the loss of Hsf1 improved survival and reduced infarct size following MI. However, its deletion did not affect inflammatory processes until 7 days post-MI or improved cardiac function in our specific murine MI model.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/41158 |
| Date | 02 October 2020 |
| Creators | Hota, Supriya |
| Contributors | Liu, Peter |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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