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Review
. 2024 Aug 9;15(8):579.
doi: 10.1038/s41419-024-06928-8.

Untangling the role of RhoA in the heart: protective effect and mechanism

Shigeki Miyamoto  1
Affiliations
Review

Untangling the role of RhoA in the heart: protective effect and mechanism

Shigeki Miyamoto. Cell Death Dis. .

Abstract

RhoA (ras homolog family member A) is a small G-protein that transduces intracellular signaling to regulate a broad range of cellular functions such as cell growth, proliferation, migration, and survival. RhoA serves as a proximal downstream effector of numerous G protein-coupled receptors (GPCRs) and is also responsive to various stresses in the heart. Upon its activation, RhoA engages multiple downstream signaling pathways. Rho-associated coiled-coil-containing protein kinase (ROCK) is the first discovered and best characterized effector or RhoA, playing a major role in cytoskeletal arrangement. Many other RhoA effectors have been identified, including myocardin-related transcription factor A (MRTF-A), Yes-associated Protein (YAP) and phospholipase Cε (PLCε) to regulate transcriptional and post-transcriptional processes. The role of RhoA signaling in the heart has been increasingly studied in last decades. It was initially suggested that RhoA signaling pathway is maladaptive in the heart, but more recent studies using cardiac-specific expression or deletion of RhoA have revealed that RhoA activation provides cardioprotection against stress through various mechanisms including the novel role of RhoA in mitochondrial quality control. This review summarizes recent advances in understanding the role of RhoA in the heart and its signaling pathways to prevent progression of heart disease.

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Conflict of interest statement

The author declares no competing interests.

Figures

Fig. 1
Fig. 1. Regulation of RhoA activity by GPCR ligands and stress signal.
The heterotrimeric Gα12/13 protein is the most established G-protein that couples receptors to RhoGEFs to activate RhoA. In some systems, Gq protein also stimulates GEFs to activate RhoA. RhoA is also activated in response to mechanical stretch and oxidative stress. Termination of RhoA activity is regulated by GAPs and RhoGDIs. GAPs accelerate the rate of hydrolysis of GTP by RhoA and GDIs inhibit the release of GDP.
Fig. 2
Fig. 2. Downstream effectors of RhoA in the heart.
A RhoA regulates actin polymerization through ROCK, mDia and PLCε. ROCK phosphorylates and activates LIMK, leading to phosphorylation and inactivation of the actin-severing protein cofilin. mDia accelerates actin nucleation while interacting with actin filament fast-growing ends. PLCε is activated by RhoA and leads to PKD activation. PKD, in turn, phosphorylates and inhibits SSH1L, a cofilin phosphatase. B MRTF-A associates with G-actin and is thus sequestrated in the cytoplasm under resting conditions. Activation of RhoA induces polymerization of G-actin to form F-actin filaments, freeing MRTF-A to translocate to the nucleus. C YAP is activated by RhoA through actin polymerization-dependent inhibition of LATS. YAP inhibition is also mediated by PA produced by PLD and by AMOT binding to YAP. RhoA-induced F-actin accumulation displaces AMOT from YAP and promotes YAP nuclear entry.
Fig. 3
Fig. 3. RhoA in cardiomyocytes provides protection against pressure overload by regulation of compensatory hypertrophy and inhibition of cardiac dysfunction but enhances fibrosis.
RhoA is activated in response to pressure overload and contributes to the development of compensatory hypertrophy and protects the heart against cardiac dilation and contractile dysfunction. The protective effects of RhoA are mediated by YAP, ROCK1, and MRTF-A-mDia pathways. However, RhoA facilitates cardiac fibrosis possibly through activation of ROCK2 and MRTF-A.
Fig. 4
Fig. 4. RhoA in cardiomyocytes preserves mitochondrial integrity and provides protection against ischemic stress.
RhoA is activated by ischemic stress and engages multiple downstream molecules such as YAP, ROCK, MRTF-A and PLCε to activate protective kinase Akt, ERK and PKD, leading to inhibition of mitochondrial death pathways. RhoA also increases mitochondrial fission through regulation of Drp1 and enhances mitophagy through inhibition of PINK1 protein degradation to control mitochondrial quality in the ischemic heart.
Fig. 5
Fig. 5. RhoA signaling regulates PINK1/Parkin-mediated mitophagy to preserve mitochondrial integrity.
PINK1 protein stability is regulated by the molecular interaction of RhoA with PINK1. Parkin expression is transcriptionally regulated by ROCK through inhibition of N-Myc as well as YAP.
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References

    1. Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. 2015;6:187–214. 10.1002/cphy.c140055 - DOI - PubMed
    1. Triposkiadis F, Xanthopoulos A, Butler J. Cardiovascular aging and heart failure: JACC review topic of the week. J Am Coll Cardiol. 2019;74:804–13. 10.1016/j.jacc.2019.06.053 - DOI - PubMed
    1. Madaule P, Axel R. A novel ras-related gene family. Cell. 1985;41:31–40. 10.1016/0092-8674(85)90058-3 - DOI - PubMed
    1. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35. 10.1038/nature01148 - DOI - PubMed
    1. Narumiya S, Thumkeo D. Rho signaling research: history, current status and future directions. FEBS Lett. 2018;592:1763–76. 10.1002/1873-3468.13087 - DOI - PMC - PubMed

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