Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the SRF Gene in Adult Heart

Abstract

Background-Serum response factor (SRF) is a cardiac transcription factor involved in cell growth and differentiation. We have shown, using the Cre/loxP system, that cardiac-specific disruption of SRF gene in the embryonic heart results in lethal cardiac defects. The role of SRF in adult heart is unknown. Methods and Results-We disrupted SRF in the adult heart using a heart-specific tamoxifen-inducible Cre recombinase.This disruption led to impaired left ventricular function with reduced contractility, subsequently progressing to dilated cardiomyopathy, as demonstrated by serial echocardiography, including tissue Doppler imaging. The cytoarchitecture of cardiomyocytes was altered in the intercalated disks. All mutant mice died from heart failure 10 weeks after treatment. These functional and structural defects were preceded by early alterations in the cardiac gene expression program: major decreases in mRNA levels for cardiac ␣-actin, muscle creatine kinase, and calcium-handling genes. Conclusions-SRF is crucial for adult cardiac function and integrity. We suggest that the rapid progression to heart failure in SRF mutant mice results primarily from decreased expression of proteins involved in force generation and transmission, low levels of polymerized actin, and changes in cytoarchitecture, without hypertrophic compensation. These cardiac-specific SRF-deficient mice have the morphological and clinical features of acquired dilated cardiomyopathy in humans and may therefore be used as an inducible model of this disorder.

Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus

“…Moreover, deletion of SRF in the adult heart using tamoxifen-induced, Cre-mediated excision results in cardiac failure and death resulting from dilated cardiomyopathy. Consistent with the embryonic phenotypes, adult hearts absent SRF show highly disorganized sarcomeres (81). Finally, a skeletal muscle cKO of SRF (using a myogenin Cre driver) results in perinatal lethality because of dysmyofibrillogenesis in skeletal muscle (61).…”

“…For example, cardiac-restricted overexpression of either wild-type or dominant-negative SRF results in various forms of heart failure because of severe alterations in contractile gene expression (125,126). Moreover, SRF inactivation or knockdown in D. discoideum (26), Drosophila melanogaster (91), Caenorhabditis elegans (30), and Mus musculus (1,28,55,61,70,78,81,82) does not result in impaired cell proliferation. Instead, these SRF null models reveal an essential and ancient role for SRF in the organization of normal cytoskeleton and contractile systems (see below).…”

Role of serum response factor in the pathogenesis of disease

“…32,37 A similar ultrastructure phenotype is manifest in adult mouse hearts where SRF is inducibly inactivated using a tamoxifen-responsive Cre recombinase. 38 A mosaic knockout of SRF using the Desmin promoter driving Cre resulted in mutant cardiomyocytes in close apposition to wild-type cardiomyocytes. Despite the presence of some 50% SRF-positive myocytes, mosaic SRF-knockout mice showed increases in both interstitial fibrosis and heart weight to body weight, and eventually succumbed to heart failure by 11 months of age.…”

Serum response factor micromanaging cardiogenesis

“…It is not surprising that SRF activity, must also be tightly regulated through a miR-133 dependent negative feedback loop, because enhanced levels of SRF have led to dilated cardiomyopathy, while too little SRF showed that SRF activity was required for the maintenance of normal sarcomeric organization and contractility (32). Possibly, the delicate balance of miR-133 directed silencing of SRF activity in cardiac hypertrophy may be more profound in human heart disease.…”