Comparing the Influence of Angiotensin II and TGFβ1 on Cardiac Fibroblasts; Myofibroblast Plasticity and Resistance to Apoptosis

Abstract

Heart disease with attendant cardiac fibrosis carries a major societal burden in developed countries. Recent work underscores the high diversity of cardiac fibroblastsCardiac fibroblast and myofibroblastsMyofibroblast in both the healthy heart and diseased heart, and the long-term presence of activated myofibroblastsMyofibroblast in the infarct scar. Angiotensin IIAngiotensin II and Transforming Growth Factor β1 (TGFβ1) have an impact on cardiac fibroblastsCardiac fibroblast and cardiac fibrosis. Both factors serve as fibroblast activators and are implicitly involved in the pathogenesis of heart disease, but their influence of elevated fibroblast resistance to apoptosis and thus their contribution to senescence of cardiac fibroblastsCardiac fibroblast is relatively understudied. The myofibroblastic phenotype incorporates αSMA to stress fibres with attendant contractility and are hypersecretory for extracellular matrixExtracellular matrix (ECM) components. These cells facilitate both acute wound healing (infarct site) and chronic cardiac fibrosis. Quiescent fibroblasts are associated with normal myocardial tissue and provide relatively slow turnover of the ECM. Following their activation, cardiac myofibroblastsMyofibroblast (unlike dermal myofibroblastsMyofibroblast) do not always revert to their quiescent phenotype, and they may resist entry to the apoptotic phase following acute wound healing. Angiotensin IIAngiotensin II has been shown to participate in contributing to the apoptosis resistant phenotype. The literature reveals that fibroblasts may halt on the precipice of apoptosis and acquire what is commonly referred to as a senescent phenotype. Within this broad description, these cells may then persist at the site of damage by resisting apoptotic cell death, and present with specific phenotypes, which may go on to contribute to chronic cardiac fibrosis. Thus an understanding of mechanisms that enable myofibroblastsMyofibroblast to evade apoptosis is required, be it based on signalling or in the microenvironment via matrix-specific clues. While most work highlights angiotensin IIAngiotensin II and TGFβ1 as contributors to fibroblast activation far less is known about mechanisms governing novel recent findings of myofibroblastMyofibroblast deactivation (reverting to their quiescent phenotype or even a less differentiated progenitor) as well as their differentiation to adipocytes, chondrocytes and osteocytes. Thus major knowledge gaps exist, and its solution may lie in the identification of specific proteins in angiotensin or TGFβ1 signalling to allow for phenotype manipulation and apoptotic removal of profibrotic cells. The current review will provide an overview of work highlighting novel information pertaining to angiotensin IIAngiotensin II and TGFβ1 which mediate resistance to fibroblast apoptosis, fibroblast activation and deactivation.