Actin-Binding Proteins in Cardiac Hypertrophy

Abstract

The heart reacts to a large number of pathological stimuli through cardiac hypertrophy, which finally can lead to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain elusive. Actin participates in the formation of highly differentiated myofibrils under the regulation of actin-binding proteins (ABPs), which provides a structural basis for the contractile function and morphological change in cardiomyocytes. Previous studies have shown that the functional abnormality of ABPs can contribute to cardiac hypertrophy. Here, we review the function of various actin-binding proteins associated with the development of cardiac hypertrophy, which provides more references for the prevention and treatment of cardiomyopathy.

Keywords: F-actin; actin-binding proteins; cardiac hypertrophy; fetal genes.

Figure 1

General features of pathological hypertrophy. Examples of pathological stimuli (such as hypertension and diabetes) responsible for cardiac hypertrophy.

Figure 2

Profilin-1 mediates cardiac hypertrophy. In normal cardiomyocytes, profilin-1 is at a basal level and the fetal genes are not activated. Pathological stimuli increase the protein level of profilin-1, which results in ERK1/2 activation, F-actin accumulation and eNOS inhibition. This results in the reactivation of hypertrophy-related genes, inhibition of autophagy and damage to sarcomere structure and, ultimately, the development of cardiac hypertrophy.

Figure 3

Proposed roles of cofilin-2 in cardiac hypertrophy. Neurohumoral factors (e.g., Ang II, ET 1 and leptin) lead to cofilin-2 phosphorylation through the RhoA/ROCK/LIMK signaling pathway. Phosphorylated cofilin-2 can lead to F-actin accumulation, which may subsequently contribute to cardiac hypertrophy through disrupting autophagy. In addition, it promotes the activation of ERK1/2 and p38, which contributes to the inhibition of autophagy and the reactivation of hypertrophy-related genes, which subsequently cause cardiac hypertrophy.

Figure 4

Domain structure and activation of mDia1. The interaction between FH3 and DAD causes mDia1 to remain in a closed and inactive conformation. GTP-loaded Rho can activate mDia1 through binding to the N-terminal GBD, which causes mDia1 to adopt an open and active form. The illustrated molecules are not drawn to scale.

Figure 5

CapZ regulates cardiac hypertrophy. Mechanotransduction leads to the activation of RhoA/Rho-kinase pathway through integrins, which reduce the binding affinity of CapZ and F-actin. It subsequently causes cardiac hypertrophy.