Mammalian enabled (Mena) is a critical regulator of cardiac function

Abstract

Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena(-/-)) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena(-/-) mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena(-/-) hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena(-/-) mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction.

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

“…However, YY1 over-expression results in cardiac dysfunction and activation of the pathologic gene program in males but not in females. Previous work has shown that YY1 increases activity of the androgen receptor [13] , and increased expression of the androgen receptor results in higher Mena levels [14], a protein highly expressed in human and animal models of heart failure [15]. We show that Mena levels are higher in the failing male human heart and YY1-transgenic mouse males, but not in the failing female human heart or female YY1-transgenic mice.…”

“…YY1 has been shown to potentiate the transcriptional activity of the androgen receptor [13], and transgenic mice over-expressing the androgen receptor have increased expression of mammalian enabled (Mena) [14], a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology [15]. As shown in Figure 3A, Mena expression is higher in male but not female YY1 transgenic mice than transgenic negative controls.…”

“…However, proper experiments to demonstrate that this is a Mena-dependent effect have not been performed and would require crossing of YY1 to a conditional Mena knockout mouse model. Interestingly, knockout of Mena results in cardiac dysfunction [15] and transgenic over-expression exacerbates heart failure [23], suggesting that Mena levels are tightly regulated in the heart. In addition, Mena is highly expressed in the young heart, and its expression is diminished in an age-related manner.…”

Repression of the Central Splicing Regulator RBFox2 Is Functionally Linked to Pressure Overload-Induced Heart Failure

“…Importantly, these genes have also been previously linked to dilated cardiomyopathy (Aguilar et al, 2011; Bienengraeber et al, 2004; Gehmlich et al, 2007; Yung et al, 2004). …”

The Possible Role of Mena Protein and Its Splicing-Derived Variants in Embryogenesis, Carcinogenesis, and Tumor Invasion: A Systematic Review of the Literature

“…Similar to studies related to breast tumor cell cultures, in case of cardiac embryogenesis, VASP, Mena, and E-cadherin were colocalized in the intercalated disk, and the authors suggested that Mena could not only be implied in actin remodeling but also in intercellular communication [24, 29]. This role was also proved in the adult knockout mice Mena−/− that presented low levels of vinculin, another adherence junction protein, when compared with the wild-type mice [30]. …”