Abstract
Hypoxic injury to the heart results in cardiac fibrosis that leads to cardiac dysfunction and heart failure. SNAIL1 is a zinc finger transcription factor implicated in fibrosis following organ injury and cancer. To determine if the action of SNAIL1 contributed to cardiac fibrosis following hypoxic injury, we used an endogenous SNAIL1 bioluminescence reporter mice, and SNAIL1 knockout mouse models. Here we report that SNAIL1 expression is upregulated in the infarcted heart, especially in the myofibroblasts. Utilizing primary cardiac fibroblasts in ex vivo cultures we find that pro-fibrotic factors and collagen I increase SNAIL1 protein level. SNAIL1 is required in cardiac fibroblasts for the adoption of myofibroblast fate, collagen I expression and expression of fibrosis-related genes. Taken together this data suggests that SNAIL1 expression is induced in the cardiac fibroblasts after hypoxic injury and contributes to myofibroblast phenotype and a fibrotic scar formation. Resultant collagen deposition in the scar can maintain elevated SNAIL1 expression in the myofibroblasts and help propagate fibrosis.
Highlights
Hypoxic injury to cells and organs, such as occurs to the heart during myocardial infarction due to artery occlusion, has been viewed as a wound healing process[1]
To determine whether SNAIL1 expression in the heart was induced in response to ischemic cardiac injury, we made use of a previously described SNAIL1-Click Beetle Red (CBR) fusion bioluminescence reporter mouse (Fig 1A)[18]
Fibrogenic gene expression (e.g., collagen I and III, Connective Tissue Growth Factor (CTGF), Interleukin 6 (IL6), Transforming Growth Factor beta (TGFβ) and periostin increased in the infarct region (Fig 1F)
Summary
Hypoxic (ischemic) injury to cells and organs, such as occurs to the heart during myocardial infarction due to artery occlusion, has been viewed as a wound healing process[1]. Hypoxia causes death of cardiac cells and these dying cells release inflammatory mediators that result in an inflammatory response in the injured region. This inflammatory response sets up a wound healing cascade which deposits a fibrous scar tissue in the infarcted region. When the scarring reaction is persistent this can lead to excess deposition of extracellular matrix (ECM) and cardiac fibrosis, which results in stiffening of the heart, reduced cardiac output (ventricle dysfunction), and heart failure[1]. Understanding of the mechanisms for and regulation of cardiac fibrosis following injury could result in the development of anti-fibrotic therapies to improve quality of life after myocardial infarction
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