Profilin is widely expressed in most eukaryotes and has a molecular weight of about 17 kDa [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 [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 [20,41,42,43].

Profilin-1 is directly associated with cardiac hypertrophy [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 [45,46]. It has been shown that the protein level of profilin-1 is significantly increased in mammalian hypertrophic hearts (Figure 2). 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 [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 [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 [44]. Increased phosphorylation of ERK1/2 activates the mechanistic (mammalian) target of rapamycin complex 1 (mTORC1) that subsequently inhibits autophagy [48,49,50]. It may be a potential key mechanism of cardiac hypertrophy mediated by the dysregulation of profilin-1 (Figure 2). 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 [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 [44]. These processes can be reversed by inhibiting the expression of profilin-1 [17]. The inhibition of profilin-1 expression in H9c2 cells and Sprague–Dawley rats can attenuate cardiac hypertrophy induced by AEGs [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 [44].

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) [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 [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 3) [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 [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 [59,60], endothelin 1 [19] and leptin [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 [19,61,62,63,64]. Y-27632 [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) [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 [13].

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 [11,65].

2.4. CapZ