The microfilament cytoskeleton is mainly composed of actin and actin-binding proteins (ABPs). Actin is one of the most abundant cytoskeletal proteins in eukaryotes and is involved in cell morphology change, migration, division and other cellular processes ^[1][2][9,10]. Actin takes two forms in cells: actin monomers (also known as globular actin, G-actin) and actin filaments (also known as filamentous actin, F-actin). Actin dynamics are finely regulated by a variety of ABPs (Table 1) ^[3][11]. Actin is involved in the formation of sarcomeres in cardiomyocytes ^[4][12]. The straight and uniform sarcomeric F-actin is critical for the contractile function of muscle ^[5][13]. In addition, actin assembly is thought to be related with autophagy ^[6][7][14,15]. The inhibition of F-actin disassembly can suppress autophagosome formation ^[8][16]. Several studies have found that F-actin is significantly accumulated abnormally in hypertrophic cardiomyocytes ^[9][10][11][17,18,19]. The dysregulation of F-actin accumulation may lead to cardiac hypertrophy through disrupting autophagy and sarcomeric structure. The function of ABPs in the development of cardiac hypertrophy has been gradually elucidated.

Types	ABPs	Basic Function	Refs.
G-actin-binding	Profilin, thymosin β4, cofilin	Bound to G-actin	[3][12][13][11,20,21]
F-actin-binding	Dystrophin, tropomyosin	Bound to F-actin	[1][3][14][9,11,22]
Actin-nucleating	Formin, Arp2/3 complex, proteins with tandem WH2 domains, leiomodin	Nucleation to initiate actin polymerization	[3][15][16][17][11,23,24,25]
Actin-elongating	Formin, tetramers of Ena/VASP	Regulation of actin assembly	[3][16][11,24]
Actin-bundling	Fimbrin/Plastin, hhLIM, gelsolin	Causes parallel F-actin filaments to closely pack together	[18][19][20][21][26,27,28,29]
Severing	ADF/cofilin, gelsolin, twinfilin, FRL-α, INF-2	Severs F-actin	[22][23][24][25][26][30,31,32,33,34]
Capping	Twinfilin, gelsolin, tropomodulin, CapZ, Arp2/3 complex	Caps F-actin to inhibit actin polymerization	[3][27][28][29][11,35,36,37]
Motor	Myosin	Cargo transfer	[30][38]

2. ABPs in Cardiac Hypertrophy

2.1. Profilin-1

Profilin is widely expressed in most eukaryotes and has a molecular weight of about 17 kDa ^[31][39]. There are various profilin isoforms expressed in different tissues. Profilin-1 is universally expressed, profilin-2 is specifically expressed in the brain and profilin-3 and profilin-4 are specifically expressed in kidney and testis, respectively ^[32][40]. Profilin accelerates the nucleotide exchange of G-actin and delivers ATP-G-actin to the growing barbed ends of F-actin through interacting with the poly-proline motifs of formin, vasodilator-stimulated phosphoprotein (VASP) and CDC42-activated Wiskott Aldrich syndrome protein (WASP)/WASP family ^{[12][33][34][35]}[20,41,42,43]. Profilin-1 is directly associated with cardiac hypertrophy ^[36][44]. Overexpression of profilin-1 in the vascular tissues of FVB/N mice leads to vascular remodeling and hypertension by increasing actin aggregation, which provides mechanical stress for the development of cardiac hypertrophy ^[37][38][45,46]. It has been shown that the protein level of profilin-1 is significantly increased in mammalian hypertrophic hearts (Figure 12). The myocardin-related transcription factor megakaryoblastic leukemia (MKL) induces the expression of the signal transducer and activator of transcription 1 (STAT1) via its SAP-domain (SAF-A/B, acinus and PIAS protein domain) activity, which upregulates PFN expression ^[39][47]. Whether this is the explanation for the increased protein level of profilin in cardiac hypertrophy remains to be investigated. In cardiomyocytes, the functional abnormality of profilin-1 can change the abundance or activity of multiple proteins associated with cardiomyopathy. For example, the overexpression of profilin-1 can contribute to decreases in the phosphorylation level of endothelial nitric oxide synthases (eNOS) at Ser1177 in the hearts of spontaneous hypertensive rats ^[9][17]. Levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), skeletal muscle α-actin (α-SMA) and phosphorylated ERK1/2 (active form) were significantly increased in neonatal rat ventricular myocytes (NRVMs) following stimulation by phenylephrine or endothelin 1, which can be inhibited by siRNA-directed PFN1 silencing ^[36][44]. Increased phosphorylation of ERK1/2 activates the mechanistic (mammalian) target of rapamycin complex 1 (mTORC1) that subsequently inhibits autophagy ^[40][41][42][48,49,50]. It may be a potential key mechanism of cardiac hypertrophy mediated by the dysregulation of profilin-1 (Figure 12). Additionally, the inhibition of Rho-associated coiled-coil-containing protein kinase pathway (ROCK) can suppress the upregulation of profilin-1 induced by advanced glycation end products (AEGs) in H9c2 cells ^[43][51]. By comparison, overexpression of PFN1 results in the reactivation of fetal genes (NPPA and NPPB), an increase in F-actin in myocardium and destruction of myofibrils ^[36][44]. These processes can be reversed by inhibiting the expression of profilin-1 ^[9][17]. The inhibition of profilin-1 expression in H9c2 cells and Sprague–Dawley rats can attenuate cardiac hypertrophy induced by AEGs ^[43][44][51,52]. In Drosophila, myocyte-specific overexpression of profilin leads to disorders in muscle fibers and sarcomeres, which result in damaged muscle ultrastructure and function ^[36][44].

2.2. ADF/Cofilin

Actin-depolymerizing factor (ADF)/cofilin consists of a single ADF homologous domain and has a molecular weight of about 15 kDa. The ADF/cofilin family contains ADF (also known as destrin, mainly expressed in endothelial and epithelial cells) and two cofilin isoforms (cofilin-1 is universal and cofilin-2 is cardio-specific) ^[45][46][53,54]. ADF/cofilin can bind to both G-actin and F-actin and can sever and depolymerize F-actin in regulating actin dynamics, which contributes to the cell contractility power ^[47][55]. The activity of cofilin is regulated by phosphorylation primarily from the ROCK/Lin-11, Isl1 and MEC-3 domain kinase (LIMK)/cofilin signaling pathway (Figure 23) ^[48][49][56,57]. Cofilin is inactivated via phosphorylation. The abundance change in cofilin-2 does not play a role in the morphogenesis of neonatal rat cardiomyocytes ^[50][58], while its activity is closely associated with the development of cardiac hypertrophy. The levels of phosphorylated cofilin-2 are increased in myocardial hypertrophy through the activation of LIM-kinase (LIMK) by ROCK, which is induced by multiple neurohumoral factors, such as angiotensin II ^[51][52][59,60], endothelin 1 ^[11][19] and leptin ^[10][53][18,61]. In hypertrophic cardiomyocytes, the increase in levels of phosphorylated cofilin-2 results in an increase in F-actin/G-actin ratios and the levels of phosphorylated ERK1/2 and p38 ^{[11][53][54][55][56]}[19,61,62,63,64]. Y-27632 ^[11][19], an inhibitor of ROCK, can reduce the levels of phosphorylated cofilin-2 through the inhibition of ROCK activity, which attenuates endothelin-1-induced neonatal cardiomyocyte hypertrophy, whereas this is achieved in ginseng (Panax quinquefolius) ^[54][62] through inhibition of p115Rho guanine nucleotide exchange factor (GEF) activity, which inhibits leptin-induced cardiac hypertrophy. In addition, WD-repeat domain 1 (WDR1), a major cofactor of the ADF/cofilin, has been reported to protect myocardium from myocardial hypertrophic stimuli ^[5][13].

2.3. Formin

Formin is a type of multidomain protein consisting of 7 subfamilies and 15 members in human genes. Formins are characterized by the presence of two conserved domains: formin homology 1 (FH1) and FH2. FH1 binds to the profilin–actin complex via poly-proline sequences and brings the G-actin to FH2, which promotes actin nucleation and polymerization ^[3][57][11,65].

2.4. CapZ

CapZ, a type of capping protein, anchors F-actin to the Z disc and regulates actin turnover, which contributes to sarcomere structural changes ^[58][59][76,77]. PIP2, a downstream effector of RAC1, can promote the dissociation of CapZ from F-actin by weakening their binding affinity ^[60][61][62][78,79,80]. Overexpression of CapZ in transgenic mice can lead to fatal cardiac hypertrophy ^[59][77]. It has been shown that hypertrophic agonists, phenylephrine or endothelin can reduce the binding affinity between CapZ and F-actin via PIP2-dependent pathways in NRVMs ^[63][81]. This may result in sarcomere remodeling, which induces cardiac hypertrophy. The cyclic mechanical strain activates downstream focal adhesion kinase (FAK) via the mechanotransduction of integrin, which then activates phosphatidylinositol 4-phosphate 5-kinase (PIP5K) through the RhoA/ROCK pathway. PIP5K phosphorylates phosphatidylinositol 4-phosphate (PI4P) in order to produce PIP2, which reduces the affinity of CapZ and F-actin binding, which contributes to the dysregulation of F-actin assembly and cardiac hypertrophy (Figure 35) ^{[62][64][65][66]}[80,82,83,84].