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• W4377029041 abstract "<b>Abstract ID 24546</b> <b>Poster Board 103</b> G protein-coupled receptor kinase 2 (GRK2) is upregulated in the injured heart, contributes to heart failure (HF) pathogenesis and has emerged as a therapeutic target for cardiac disease. One approach used to target GRK2 activity in murine HF models involves the genetic expression of peptide inhibitors via C- or N- terminal fragments of GRK2. Herein, we subjected transgenic mice with cardiac restricted expression an N-terminal fragment of GRK2 (βARKnt) to pressure overload and found that these mice exhibit sexual dimorphism in HF and atrial susceptibility. This recapitulates the clinical data indicating essential differences between men and women in HF type, epidemiology and pathophysiology. Men are predisposed to the development of HF with reduced ejection fraction due to heart-related conditions. Women, meanwhile, have a higher incidence of HF with preserved ejection fraction due to comorbidities and sex-related factors. The poor inclusion of females in clinical trials and murine studies has contributed to a poor understanding of disease behavior in women. This study carefully dissects both the acute and chronic responses of non-transgenic and βARKnt female mice to trans-aortic constriction (TAC) surgery, and whether they differ from our previous observance in males. Interestingly, while left ventricular (LV) posterior wall thickness during diastole and systole and cardiac ejection fraction were all significantly higher in βARKnt mice prior to surgery, our data demonstrate proportional LV hypertrophic growth in both the βARKnt and non-transgenic mice in response to acute cardiac stress. During chronic stress, in contrast to non-transgenic male mice that transition to heart failure from 10-14 weeks after TAC, ejection fraction was indistinguishable between non-transgenic Sham and TAC females, with elevated yet consistent levels in the βARKnt TAC and more-so Sham females. βARKnt female mice exhibited a robust and continual increase in asymmetric hypertrophy across the 14 week time course. This is in contrast to non-transgenic female mice that have mild, stable and symmetric hypertrophic growth. This is also in contrast to the stable hypertrophy and cardioprotection observed in βARKnt male mice, and opposite to the switch from hypertrophy to wall thinning observed in non-transgenic male mice transitioning into maladaptive remodeling and dilated cardiomyopathy. Additionally, lung weight normalized to tibia length was only elevated in the βARKnt TAC female mice, suggesting pulmonary congestion. Analysis of Masson’s Trichrome and WGA staining demonstrated that unlike in βARKnt male mice, fibrosis and cardiac hypertrophy are evident in βARKnt female mice at baseline and more pronounced following acute and chronic pressure overload stress. Further, these data suggest an increase in immune cell infiltration that is under further investigation. Data in our male mice suggested enhanced metabolic flexibility as part of the mechanism of cardioprotection by βARKnt; however, the opposite was observed in females. Alternatively, RNAseq data suggests dysregulation of phagosome formation and wound healing responses as possible mechanisms for the increased pathological remodeling in our βARKnt female mice that will serve as a focus of ongoing and future studies. Overall, increasing<b></b> our knowledge about the underlying molecular mechanisms involved in the male versus female failing heart will contribute to more effective sex-specific therapeutic strategies." @default.
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• W4377029041 date "2023-05-18" @default.
• W4377029041 modified "2023-09-29" @default.
• W4377029041 title "Sex-dependent Differences in Pressure Overload Hypertrophy in NT-GRK2 Mice" @default.
• W4377029041 doi "https://doi.org/10.1124/jpet.122.245460" @default.
• W4377029041 hasPublicationYear "2023" @default.
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