RAS inhibition in resident fibroblast biology

Abstract

Angiotensin II (Ang II) is a primary mediator of profibrotic signaling in the heart and more specifically, the cardiac fibroblast. Ang II-mediated cardiomyocyte hypertrophy in combination with cardiac fibroblast proliferation, activation, and extracellular matrix production compromise cardiac function and increase mortality in humans. Profibrotic actions of Ang II are mediated by increasing production of fibrogenic mediators (e.g. transforming growth factor beta, scleraxis, osteopontin, and periostin), recruitment of immune cells, and via increased reactive oxygen species generation. Drugs that inhibit Ang II production or action, collectively referred to as renin angiotensin system (RAS) inhibitors, are first line therapeutics for heart failure. Moreover, transient RAS inhibition has been found to persistently alter hypertensive cardiac fibroblast responses to injury providing a useful tool to identify novel therapeutic targets. This review summarizes the profibrotic actions of Ang II and the known impact of RAS inhibition on cardiac fibroblast phenotype and cardiac remodeling.

Keywords: Angiotensin II; Angiotensin converting enzyme inhibitor; Angiotensin receptor antagonist; Fibroblast; Fibrosis.

Figure 1.. RAS-mediated mechanisms of cardiac fibroblast activation.

Angiotensin II (Ang II) binds angiotensin type 1 receptors (AT1R) on the fibroblast to initiate three key processes that result in fibroblast activation: fibrogenic gene upregulation, immune cell recruitment, and oxidative stress. Crosstalk between components of each pathway supports redundant feed forward mechanisms that together with cell death resistance perpetuate activated fibroblasts with cardiac injury. Transforming growth factor-beta (TGF-β), scleraxis (SCX), signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase 1/2 (ERK1/2), cellular communication network factor 2 (CCN2), osteopontin (OPN), periostin (POSTN), alpha-smooth muscle actin (α-SMA), toll-like receptor 2 (TLR2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), NADPH oxidase (NOX4), reactive oxygen species (ROS), B-cell lymphoma 2 (Bcl-2). Created with BioRender.com.

Figure 2.. RAS inhibition reduces cardiac fibrosis and improves outcomes after chronic or acute injury.

Hypertension and cardiac injury (e.g. myocardial infarction) induce changes in the heart that result in cardiac fibrosis, impaired function, and increased mortality. These insults impact several cell types resulting in cardiomyocyte hypertrophy, fibroblast proliferation and activation, and immune cell recruitment to the heart. Together, the adaptive responses of cardiac cells cause heart wall thickening and extracellular matrix production that reduce cardiac contractility and output that are attenuated by RAS inhibition. Created with BioRender.com.

Figure 3.. Current knowledge gaps and future areas of study.

Important foci for future investigation are highlighted.