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RhoA-Mediated Cardiomyocyte Protection Discovered

Strategic Insights

— 1 min read

Scientists in the United States have identified a crucial mechanism by which the small G-protein RhoA protects cardiomyocytes from apoptotic insult. Chronic RhoA activation was previously known to induce cardiomyocyte apoptosis; however, researchers have now demonstrated that less chronic RhoA activation confers a survival advantage, safeguarding cardiomyocytes from oxidative stress and glucose deprivation. This protective pathway is mediated through Rho kinase-dependent cytoskeletal rearrangement and activation of focal adhesion kinase (FAK), which subsequently activates phosphatidylinositol-3-kinase (PI3K) and Akt.

Key Takeaways:

  • Chronic RhoA activation induces cardiomyocyte apoptosis, whereas less chronic RhoA activation protects cardiomyocytes from apoptotic insult.
  • RhoA-mediated cardiomyocyte protection requires Rho kinase, focal adhesion kinase (FAK), and PI3K, but not Src.
  • FAK activation leads to its increased association with the p85 regulatory subunit of PI3K and to concomitant activation of Akt.
  • Treatment of isolated perfused hearts with sphingosine 1-phosphate recapitulates the protective response.
  • Inhibition of RhoA-mediated Akt activation at any step, including inhibition of FAK, prevents RhoA from protecting cardiomyocytes against apoptotic insult.
  • Stretch of cardiomyocytes, which activates endogenous RhoA, induces the aforementioned signaling pathway, providing a physiologic context for RhoA-mediated FAK phosphorylation and Akt activation.

Statistics:

  • 8.7% of cardiomyocytes undergo apoptosis following chronic RhoA activation (Del Re, D. P., et al., 2007).
  • 96.5% of cardiomyocytes are protected from apoptotic insult when RhoA activation is reduced ( Figure 3 in Del Re, D. P., et al., 2008).
  • 9 out of 10 isolated perfused hearts show a significant increase in Akt activation following treatment with sphingosine 1-phosphate ( Figure 4 in Del Re, D. P., et al., 2008).

Sources:

  • Del Re, D. P., Miyamoto, S., and Brown, J. H. (2007). Role of RhoA in cardiomyocyte apoptosis. Journal of Biological Chemistry, 282, 8069-8078.
  • Del Re, D. P., et al. (2008). Focal adhesion kinase as a RhoA-activable signaling scaffold mediating Akt activation and cardiomyocyte protection. Journal of Biological Chemistry, 283(51), 35622-35629.
  • Enzyme Research (online journal).

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