Renin - Angiotensin - Aldosterone System and TGF - β Signaling in the Hypertrophic Heart


Cardiac hypertrophy and remodeling are pathological features of many cardiac diseases, with underlying causes including hypertension, cardiomyopathy, valvular dysfunction, and myocardial infarction. In these diseases, ventricular hypertrophy occurs in response to pathological stimuli such as pressure and volume overload, sarcomere gene mutations, and neurohumoral activation, and a major consequence of prolonged and uncontrolled hypertrophic remodeling is cardiac dysfunction, which can lead to heart failure or cardiac arrest resulting from arrhythmia. Despite the various pathological stimuli, there are many common features in the hypertrophic response in different cardiac diseases. In addition to increased cardiomyocyte mass, sarcomere rearrangement, and extracellular matrix deposition, other common features have recently been appreciated, including inflammatory signaling and immune cell activation. Numerous cell types are involved in orchestrating this complex pathological response. The heart consists of a heterogeneous population of cells, including cardiomyocytes and noncardiomyocytes, and it is now clear that intercellular signaling and communication between these cell types are critical in the pathophysiology of ventricular hypertrophy and remodeling (Figure 1). Noncardiomyocytes display phenotypic changes during the development of cardiac hypertrophy. There is still much to be revealed about the specific roles of these cell types and their overall contribution to the hypertrophic response. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) and neurohumoral factors such as angiotensin II and aldosterone are involved in the pathophysiology and correlate with disease progression, but the cell type–specific targets and their effects on the cardiomyocyte in vivo are not well understood. The influence of both resident and infiltrating immune cells during myocardial infarction and postinfarction remodeling is well recognized. Recently, it has been shown that myeloid cell phenotypes play a critical role in ventricular hypertrophy and remodeling. In addition, there is a small body of literature examining specific immune cell interactions in other models of ventricular hypertrophy such as pressure overload. Although the early phases of myocardial infarction are dissimilar to the pathophysiology of progressive, chronic hypertrophy, studies focusing on the later phase of postinfarct hypertrophic remodeling may provide some insight into potential cellular mechanisms and therapeutic targets. In this review, we summarize the current understanding of the role of noncardiomyocytes in the pathogenesis of cardiac hypertrophy, placing particular emphasis on relevant immune cell interactions and inflammatory signaling mechanisms. We highlight seminal findings demonstrating the importance of specific cell types in regulating the cardiomyocyte hypertrophic response, and we emphasize the relevant current and potential therapeutic targets. It is clear that this field is not fully developed and deserves increased attention.

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@inproceedings{Frieler2015ReninA, title={Renin - Angiotensin - Aldosterone System and TGF - β Signaling in the Hypertrophic Heart}, author={Ryan A . Frieler and Martin Mortensen}, year={2015} }