Cardiomyocyte-derived fibrosis as driver of cardiomyopathy

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This editorial refers to ‘Cardiomyocyte SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition’, by L.T. Timmer et al., https://doi.org/10.1093/cvr/cvaf021. Cardiac fibrosis describes pathological deposition of extracellular matrix (ECM), which can either be the consequence of cardiomyocyte death in ‘replacement fibrosis’ or emerge as ‘reactive fibrosis’ during mechanical or metabolic overload in the absence of significant cardiomyocyte death. Excessive fibrosis and its chronification inevitably lead the progression of heart failure, mainly due to stiffening of the myocardium and predisposition to lethal arrhythmia. To identify new therapeutic strategies, underlying mechanisms and cell types need to be deciphered by basic research. Sorbin and SH3 domain containing 2 (SORBS2) or ArgBP2 is an adaptor protein that assist in the interaction between many cytoskeletal and membrane-associated proteins.1 SORBS2 is highly expressed in the heart, where it is mainly found in cardiomyocytes and in vascular smooth muscle cells. In cardiomyocytes, SORBS2 is confined to the costamere, which are connected to the sarcomeric Z-disc by actin filaments and to the intercalated disc, which constitutes the connection to the neighbouring cardiomyocytes.1 Mutations in SORBS2 are linked to different cardiomyopathies, and high levels of cardiac SORBS2 are observed in patients with heart failure. Mechanistically, cardiac SORBS2 has been associated with microtubule stability2 and conduction anomalies.2,3 In this issue, Timmer et al.4 reported a novel mechanistic role of cardiac Sorbs2 to protect against cardiac hypertrophy, dysfunction, and reactive fibrosis. In order to specifically identify Sorbs2 as stress-induced gene in mouse and human cardiomyocytes, the authors employed an innovative approach by combining the analysis of single-cell transcriptome data sets of failing cardiac tissue from humans and mice in combination with a rank-based comparison to pinpoint genes most strongly correlating with the cardiomyocyte stress gene Nppa. They verified strong induction of Sorbs2 RNA and protein at multiple time points in cardiomyocytes after transverse aortic banding (TAB), at the border zone after myocardial infarction in mice as well as in human failing hearts. In mice after TAB and in humans with dilated cardiomyopathy, the increase in Sorbs2 expression was closely correlated to cardiac dysfunction, remodelling, and fibrosis. Importantly, a specific, conserved transcriptional start site was identified that drives stress-induced Sorbs2 transcripts by the transcription factor GATA4. To assess the functional impact of SORBS2, Timmer et al. generated adult-onset cardiomyocyte-specific Sorbs2 knock-out (KO) mice. While at baseline, the lack of Sorbs2 induced cardiomyocyte hypertrophy and a trend towards more fibrosis, pressure overload by TAB strongly worsened fibrosis, triggered systolic dysfunction and concentric ventricular remodelling in Sorbs2 KO mice. Mechanistically, the authors identified exaggerated ECM deposition and a higher degree of collagen crosslinking as main driver of heart failure in Sorbs2 KO mice after TAB, which is in line with a previous report identifying early fibrosis before cardiac dysfunction develops as culprit of cardiomyopathy in another mouse model of Sorbs2 KO.2 But what is the reason for exaggerated fibrosis? The authors searched for Sorbs2 interaction partners in the heart and identified proteins from the interface of integrins and the cytoskeleton (e.g. vinculin, zyxin, and Wasp2), but also protein homeostasis (e.g. ribosomal proteins), signalling, or metabolism-related proteins. Integrins are transmembrane receptors that connect the ECM to the cellular cytoskeleton and enable the detection of increased mechanical load.5 During cardiac overload, aggravated mechanical forces pull on the ECM and are transduced by integrins to the cardiomyocyte actin cytoskeleton and towards the nucleus, ultimately impacting gene expression. In addition, ECM proteins act as agonist at integrins to initiate ‘outside-in’ signalling, which promotes cardiomyocyte survival and hypertrophy.5 SORBS2 as adaptor protein might constitute an essential connection to enable transmission of signals received by integrins, which is no longer possible in its absence. Transcriptomic profiling by the authors consequently revealed up-regulation of genes related to integrins and ECM in Sorbs2 KO mice.4 We would like to propose that this gene expression pattern might reflect a feedback mechanism, whereby the interrupted signal transmission downstream of integrins leads to up-regulation of matrix proteins (acting as agonists on integrins), as well as integrins themselves in an effort by cardiomyocytes to restore signalling input from the ECM, although that ultimately leads to fibrosis. Further analysis revealed the term ‘epithelial to mesenchymal transition’ (EMT) to be enriched among genes dysregulated in Sorbs2 KO mice at baseline as well as during TAB. In heart failure, a special form of EMT, endothelial to mesenchymal transition/activation, which is transient in nature, was shown to promote myocardial fibrosis, whereby capillary endothelial cells secrete matrix proteins, but also activate fibroblasts.6 Although Timmer et al. did not investigate this possibility, it could contribute to fibrosis in Sorbs2 KO mice. However, and more likely in this cardiomyocyte-specific KO model, the cardiomyocytes themselves express EMT genes. Indeed, cardiomyocyte EMT-like processes had been previously demonstrated and are associated with cardiomyocyte de-differentiation, hypertrophy and dysfunction, up-regulation of many matrix genes, secreted growth factors, and transmembrane proteins in cardiomyocytes, many of which are also up-regulated in the Sorbs2 KO mice (e.g. Postn, Tnc, Vcan, ItgaV, Thbs1, Itgb5, Col12a1, and others).7 Intriguingly, Nmrk2, strongly up-regulated in Sorbs2 KO mice, was shown to counteract terminal differentiation in myoblasts, although this was so far not studied in cardiomyocytes.8 Therefore, we suggest that cardiomyocytes are the main culprit of fibrosis in the Sorbs2 KO model. Indeed, previous work had shown a strong and persistent up-regulation of collagen genes and pro-fibrotic growth factors like Ctgf and Tgfb2 in isolated cardiomyocytes after TAB.9 Very likely, however, the cardiomyocytes in addition to their own matrix production will engage fibroblasts as specialized cells for this purpose, for example, via secreted growth factors such as Igfbp5 or Tgfb2 and Tgfb3, which were all induced in Sorbs2 KO mice according to Timmer et al.4 and the accompanying data. To prove this hypothesis, cardiac single-cell sequencing should be conducted in Sorbs2 KO and control mice in the future, to decipher changes in intercellular interactions, especially between cardiomyocytes and fibroblasts. Furthermore, it should be tested whether ablation of cardiomyocytes TGFb2/3, both strong drivers of pathological fibrosis, could improve the phenotype of Sorbs2 KO mice.10 Perhaps more importantly, previously introduced anti-TGFβ2/3 strategies could be probed as translational approach to oppose fibrosis in patients with mutations in SORBS2 or other genes related to integrin signalling.10 Therefore, the study by Timmer et al. might be the first step towards personalized therapy in a subgroup of cardiomyopathy patients. A. M.-G. and J.H. are supported by the CRC1550/1-B01 from the Deutsche Forschungsgemeinschaft. There are no new data associated with this article.

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