The Preconditioning of Zebrafish Heart Regeneration by Tactile Cardiac Stimulation


Student thesis: Doctoral Thesis

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Award date28 Jun 2019


Heart attacks take the lives of many individuals worldwide, and heart failure is one of the most prevalent diseases in the world. Cardiologists and scientists have attempted to discover different ways to inhibit or treat these health issues. Heart preconditioning is one of the very well-known methods for the prevention and treatment of heart diseases. Several heart preconditioning approaches have been developed, and some of them could help decrease the scar size, reduce arrhythmias, and lessen the risk of extremely long ischemia after a heart attack.

One of the best and mostly neglected models for studying heart preconditioning is zebrafish. Zebrafish is the best model for heart regeneration because it can fully regenerate its heart in 30 days. Thus far, it has the fastest time for heart regeneration among animal models. Recently, scientists have observed that an injury to the zebrafish thoracic area can accelerate its heart regeneration. This observation could introduce zebrafish into the field of heart preconditioning; however, the mechanism of this preconditioning method is not explained in this study.

In this thesis, I introduce a mechanism to explain this preconditioning method. First, I showed that any injury to the other parts of the zebrafish body cannot induce the preconditioning effect on heart regeneration. Second, I demonstrated that tactile stimulation of the heart is necessary to induce preconditioning. Moreover, this tactile heart stimulation (touching the heart) specifically preconditions the regeneration in the heart but not the other organs. I tested several hypotheses to eliminate some factors as the triggers of heart regeneration. Some of these factors are cell death due to heart touching, electrical conductivity of the forceps, and mechanical stress and electrophysiological changes in the heart after preconditioning.

Using cytochrome c staining and transmission electron microscopy (TEM), I further proved that mitochondria are more abundant in preconditioned hearts than in intact control hearts. Furthermore, I showed that cytochrome c expression after preconditioning is heart specific.

Several studies have shown the importance of estrogen in regulating the mitochondrial function; therefore I also investigated the role of estrogen in the preconditioning effect. I showed that an estrogen inhibitor (tamoxifen) can inhibit the preconditioning effect of the sham operation. In addition, only estrogen treatment without any sham operation could successfully induce the preconditioning effect in the heart in terms of scar removal and induction of proliferating cells in the heart. This observation explains that estrogen can induce the preconditioning effect after tactile stimulation of the heart.

I also demonstrated that hypoxia-inducible factor alpha (HIF1α) is crucial for inducing the preconditioning effect. My proposed model to explain the mechanism of this preconditioning method is that after sham operation there is an upregulation of estrogen which leads to an upregulation of HIF1α. HIF1α leads to preconditioning effect. HIF1α is the downstream of estrogen since oxygen treatment can partially abolish the preconditioning and more importantly, estrogen treatment cannot reverse the inhibitory effect of oxygen.

    Research areas

  • Zebrafish, Preconditioning, Tactile cardiac stimulation