Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling

RA Frieler, RM Mortensen - Circulation, 2015 - Am Heart Assoc
Circulation, 2015Am Heart Assoc
In the past decade, there has been increasing interest in the direct role of MR activation
during pathological remodeling. In severe heart failure, clinical trials have demonstrated that
MR antagonism provides significant benefit independently of blood pressure lowering. 6 MR
is expressed in a wide range of cells, and the use of cell-specific knockout technology has
now delineated some of the cell-specific effects. Both cardiomyocyte MR and myeloid MR
have now been shown to directly influence cardiac remodeling. 2, 7, 8 TGF-β is upregulated …
In the past decade, there has been increasing interest in the direct role of MR activation during pathological remodeling. In severe heart failure, clinical trials have demonstrated that MR antagonism provides significant benefit independently of blood pressure lowering. 6 MR is expressed in a wide range of cells, and the use of cell-specific knockout technology has now delineated some of the cell-specific effects. Both cardiomyocyte MR and myeloid MR have now been shown to directly influence cardiac remodeling. 2, 7, 8 TGF-β is upregulated in the hypertrophied and fibrotic heart and is regarded as one of the major profibrotic cytokines and critical mediators of cardiac fibrosis. TGF-β has many pleiotropic effects in modulating cardiomyocyte and noncardiomyocyte function, and it induces cardiomyocyte hypertrophy and fibroblast proliferation and fibrosis. Inhibition of TGF-β signaling and genetic ablation of TGF-β have been shown to reduce fibrosis and to prevent cardiac dysfunction in several models of maladaptive cardiac remodeling, 9, 10 whereas TGF-β overexpression has been shown to induce cardiac hypertrophy. 11
In pressure overload–induced cardiac remodeling, Koitabashi et al12 found that TGF-β–neutralizing antibody reduced myocardial fibrosis without affecting hypertrophy or cardiac function. They further revealed that cardiomyocytespecific (Myh6-Cre) knockout of TGF-β receptor type II, but not type I, significantly reduced hypertrophy and fibrosis and prevented cardiac dysfunction through a TGF-β–activated kinase 1 signaling pathway. In fact, TGF-β–activated kinase 1 activation is known to induce cardiac hypertrophy; therefore, the TGF-β–TGF-β–activated kinase 1 signaling pathway may be useful for therapeutic targeting. 13 However, different TGF-β signaling pathways are context dependent because knockout of both cardiomyocyte TGF-β receptors 1 and 2 significantly ameliorated postinfarct cardiac remodeling. 14 Global blockade of TGF-β with neutralizing antibody, on the other hand, resulted in complete mortality within 5 days, suggesting that
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