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protein when coexpressed in the same cells

Further insights into cardiac role of SRF were deduced from lossand gain‐of‐function approaches in vivo in mice. Classical global deletion of Srf leads to a very early embryonic lethality in mice, with a prominent defect in mesoderm formation, which hampered further evaluation of cardiac role of SRF To overcome this problem, Parlakian et al. has generated a mutant mouse line with targeted deletion of SRF in the heart They found that mice with early depleted cardiac SRF expression display severe cardiac defects, impaired expression of critical cardiac transcription factors such as Nkx2.5/GATA4/myocardin, and die between embryonic day 10.5 (E10.5) and E13.5 of development Similarly, Miano et al., generated mice where SRF was knocked out in >80% of cardiomyocytes and >50% of vascular smooth muscle cells using SM22alpha‐Cre‐mediated excision of promoter and first exon of SRF. They also noticed both cardiac and vascular defects such as highly disorganized sarcomere, defective actin/ intermediate filament bundles, and cardiac looping resulting embryonic death at E11.5. On the other hand, disruption of SRF in adult heart using a heart‐specific Tamoxifen‐ inducible Cre recombinase led to progressive dilated cardiomyopathy and heart failure due to decreased expression of proteins involved in force generation and transmission, low levels of polymerized actin, and changes in cytoarchitecture without hypertrophic compensation Moreover, the symptoms observed in SRF‐deficient mice at adolescence resemble morphological and clinical features of acquired dilated cardiomyopathy in humans. Furthermore, cardiac‐sustained overexpression of SRF in transgenic mice is sufficient to develop cardiac hypertrophy and cardiomyopathy [whereas, overexpression of dominant‐negative form of SRF in mice causes dilated cardiomyopathy. These findings also have physiological and pathological relevance since the basal expression of SRF protein is found to be increased in old compared to young adult rat hearts and an increased expression of an alternatively spliced dominant‐negative isoform of SRF was observed in failing human hearts Taken together, findings from transgenic in vivo mouse models further strengthens the view that SRF is one of the downstream effectors of the signaling pathways involved in the induction of cardiac hypertrophy.