Mason Danna

 Introduction. Cardiovascular disease is the leading cause of death globally, and heart failure is a major component of cardiovascular related morbidity and mortality.¹ Cardiac remodeling is molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury.² Hippo signaling pathway is an evolutionarily conserved pathway that regulates organ size and cell proliferation, survival and differentiation.³ The Hippo-Yap pathway has been linked to adipogenesis, hypertrophy and fibrosis, both directly and indirectly through cross signaling of TGF-beta and WnT (wingless-related integrated site). Methods. Transgenic mice with a floxed Yap1 (yes-associated protein) allele and cre recombinase transgenic mice were used for hypertrophy studies. Aortic constriction was performed to increase pressure overload. Echocardiography was used to measure size changes.⁴ Mice with knockout of WW45, which suppresses MST1/2 (mammalian-sterile 20 like kinase) were used for regeneration studies.⁵ For fibrosis studies, mice with mixed genetic background of C57BL/6 and 129SV were given 3 mg of tamoxifen. Mice post-MI were injected with EdU (0.5 mg) 24 h before collecting heart tissue.⁶ Human samples, mouse models, and HL-1 myocytes for the study with oil red o, masson trichome and immunofluorescence staining were used for adipogenesis. Immunoblotting, coimmunoprecipitation and quantitative PCR were utilized. They generated their own recombinant lentiviruses and assessed Hippo and Wnt pathways with firefly and renilla luciferase.⁷ For regeneration studies, engineering of a viral knockdown vector of Salv for cardiomyocytes. They measured protein levels in the hearts at various time stamps after myocardial infarction.⁸  Results. Down regulation of YAP showed decreases in hypertrophy for pressure overloaded cells. Mice with knockout of WW45, which is required for activation of MST1/Lats2, showed increased cardiac dysfunction induced by pressure overload than a control group.⁴ Deletion of kinases Lats1/2, showed fibrotic response in resting cardiac fibroblasts and was even worse during exacerbations with myocardial infarction.⁶ Immunofluorescence showed reduced levels and localizations of intercalated disc proteins like PKP2 and desmoplakin (DSP) in the AC hearts. Immunoblotting showed increased expression of YAP.⁷ Deletion of Salv protein in the hippo pathway in mice with ischemic heart failure after a myocardial infarction shows better wound healing and regeneration with less fibrosis and increased vascularity and pumping function.⁸ Conclusion. Cardiac remodeling can lead to heart failure and malignant arrythmias. Hippo signaling effects the heart through hypertrophy, fibrosis, regeneration and adipogenesis and can be a target for therapies post-myocardial infarction.

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