Clin Res Cardiol (2022).

The role of the Rac1 activator Tiam1 in cardiac stress remodeling
N. Tzschöckel1, J. Pan1, M. Dewenter2, J. van Heuveln1, J. Backs2, T. Wieland1, C. Vettel1
1Experimentelle Pharmakologie Mannheim, Medizinische Fakultät Mannheim der Universiät Heidelberg, Mannheim; 2Molekulare Kardiologie und Epigenetik, Universitätsklinikum Heidelberg, Heidelberg;

The small GTPase Rac1 is a multifunctional protein that contributes to cardiac remodeling by e.g. transcriptionally regulating pro-hypertrophic and pro-fibrotic factors and by its involvement in oxidative stress generation. We have recently shown that the Gi-dependent activation of Rac1 via guanine nucleotide exchange factor (GEF) Tiam1 is essential to
α1-adrenoceptor driven hypertrophy in neonatal rat cardiomyocytes (NRCM).

To further explore the function of Tiam1 in cardiac pathophysiology in vivo and in vitro by using genetic and pharmacological approaches.

Methods and Results:
We found that Tiam1 mRNA is upregulated in cardiac tissue of patients with heart failure, and in experimental models of chronic catecholamine exposure. Mice subjected to α/β-adrenergic stimulation via a combination of isoprenaline (ISO) and phenylephrine (ISO/PE, 30 mg/kg*d for each drug) showed a significant upregulation of cardiac Tiam1 mRNA after 48-96h of exposure, paralleling hypertrophic growth measured as the increase of heart weight to tibia length ratios (HW/TL). Further investigation revealed that Tiam1 is upregulated in cardiac fibroblasts, but not endothelial cells or cardiomyocytes. To analyze the contribution of Tiam1 to hypertrophic remodeling in vivo, mice with a global Tiam1 depletion (Tiam1-KO) were subjected to 7d and 28d of chronic ISO/PE infusions. In accordance with earlier in vitro data, Tiam1-KO were markedly resistant to cardiac hypertrophy compared to WT animals. Moreover, in contrast to WT, Tiam1-KO showed preserved systolic function after 28d of exposure and no sign of lung congestion. Interestingly, protection from hypertrophy did not correlate with an attenuated expression of fetal genes; instead, we observed a significant lower induction of genes associated with cardiac fibroblast activation such as periostin, collagen1a1 and TGFβ during the phase of hypertrophic growth (6-96 h).

To investigate Tiam1 depletion or inhibition in cardiac fibroblast pathophysiology, where Tiam1 has been described to mediate Rac1 activation in response to angiotensin II (AngII) type 1 receptor stimulation, we isolated adult cardiac fibroblasts from WT and Tiam1KO mice, and applied the Tiam1 inhibitor NSC 23766 (10 µM). Tiam1 inhibition or depletion significantly impaired Ang II-induced PAK- and p38-, but not ERK1/2-phosphorylation. When subjected to 28 d of chronic Ang II (1 mg/kg*d) perfusion, Tiam1KO showed delayed hypertrophy and limited concentric cell growth, but were unprotected against ventricular fibrosis and diastolic dysfunction.

Tiam1 deficiency protects against catecholamine-induced cardiac hypertrophy and systolic dysfunction in vivo. This protective effect appears to involve attenuated fibroblast activation during the early stages of hypertrophic growth.