Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure

Abstract

Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.

Figure 1

TGFβ signals via the SMAD2/3 and SMAD1/5 pathway in cardiomyocytes. Ventricular cardiomyocytes of adult rat were stimulated with 1 ng⋅ml⁻¹ TGFβ1 for 2 h. Protein extracts of these cells were analysed by Western blots with antibodies specific against phosphoSMAD2, phosphoSMAD1/3 or phosphoSMAD1/5. Phosphorylation, which is indicative of SMAD activation, was detected for all these SMADs. *P < 0.05 versus unstimulated controls, n = 5 independent culture preparations.

Figure 2

Overview about TGFβ influence on components of cardiac remodelling in left ventricular systolic heart failure. TGFβ has been shown to promote the transition from cardiac hypertrophy to apoptosis and to regulate mitochondrial signalling molecules, miRNA expression and contractile function and fibrosis. All these processes are involved in heart failure progression.

Figure 3

Influence of TGFβ‐SMAD and TGFβ‐TAK1 signalling on adrenoceptor‐mediated pathways in LV heart failure progression. Adrenoceptors (AR) stimulate the expression of genes promoting hypertrophic growth via the transcription factor AP‐1. Under simultaneous presence of SMAD4, the pro‐hypertrophic response to adrenoceptor stimulation is shifted to a pro‐apoptotic gene transcription via AP‐1/SMAD complexes. Also, under TGFβ stimulation of cardiomyocytes, AP‐1 and SMADs mediate apoptosis. In addition to these effects on cardiomyocytes, activation of the TGFβ/SMAD pathway or induction of SMADs via β‐arrestins induces the transcription of fibrotic genes. In contrast to the SMAD pathway, TAK1 activation stimulates hypertrophic growth while inhibiting cardiac necroptosis and apoptosis by interacting with RIP1. Strong β‐adrenoceptor (ADRB) activation results in β‐adrenoceptor desensitization via β‐adrenoceptor /β‐arrestin complexes. This process can be inhibited by TGFβ. Depicted in red are switch molecules that can modulate the response of the cell to receptor stimulation and thereby influence the outcome of this stimulation on the remodelling process.

Figure 4

The central role of mitochondria in LV heart failure can be modulated by TGFβ. Hypertrophy, fibrosis and apoptosis can be controlled by mitochondria via generation of ROS. NLRP3 is a newly identified molecule that enhances mitochondrial ROS production and that is controlled by TGFβ or angiotensin II (AngII). miR181c enhances ROS production via modulation of complex IV of the respiratory chain. TOM70, acting as a repressor of mitochondrial ROS production, is found to be reduced in heart failure. This reduction then provokes enhancement of ROS. Enhancement of mitochondrial uncoupling protein during stimulation of β‐adrenoceptors by noradrenaline (NA) and TGFβ‐receptor activation results in reduced energy production and impaired contractile function. Opening of the MPTP plays a central role in the induction of apoptosis. Opening of this pore can be modulated by the accessory proteins VDAC and ANT1. Their expression is regulated by crystalline B, TGFβ, AngII, ROS and β‐adrenoceptors (ADRB). Central molecules that modulate mitochondrial processes in heart failure are depicted in red.

Figure 5

Influence of miRNAs on LV adverse remodelling can be modulated by β‐adrenoceptors (ADRBs) or TGFβ. miRNAs that have been demonstrated to reverse or promote adverse cardiac remodelling are depicted. Up‐regulation of miR15 or miR22 prevents the induction of fibrosis or apoptosis under pressure overload (TAC) or β‐adrenoceptor stimulation (ISO) while preserving effects on moderate, compensatory hypertrophy, as when these miRs are inhibited adverse remodelling develops. In contrast, up‐regulation of miR25 or miR21 under TAC enhances adverse cardiac remodelling, and down‐regulation of miR133a under TAC preserves cardiac function, whereas the overexpression of miR133a results in the development of adverse remodelling. Black arrows indicate the responses of the cell to TAC or ISO. Switch molecules in the process of adverse remodelling are depicted in red. Green arrows and symbols indicate interference of miR expression by anti‐miRs or transgenic overexpression.