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  • Growing evidence indicates that GRKs

    2023-11-20

    Growing evidence indicates that GRKs can exert different effects within the cell depending on the stimulus, cell type, and localization [97], [121]. In this sense, we were the first to demonstrate a mitochondrial localization for GRK2 [122], later confirmed by other investigators [123], establishing a functional role for GRK2 in organelle biogenesis and ATP production [122], [124].
    Sympathetic system and remodeling Histopathologic evaluation in murine hearts reveals subendocardial and interstitial fibrosis, vacuolization of calcium calmodulin dependent protein kinase and mineralization [16], [125], [126], [127]. Furthermore, morphometric analysis of cardiomyocytes demonstrates a progressive hypertrophy, increased apoptosis alongside with fibrosis and amyloid deposition [128]. Several organs undergo fibrotic remodeling as a function of age resulting in overall decreased functionality. The precise mechanisms leading to the age-dependent accumulation of collagen have yet to be fully identified. Mounting evidence reveals the emerging role of collagen cross-linkers and matrix metalloproteinases (MMP) in the turnover of collagens, finely regulated by proteolytic MMP activity and their endogenous tissue inhibitors (TIMPs) [129], [130]. All of these mechanisms are modulated by neuroendocrine activation and βAR signal transduction modifications. Indeed, chronic sympathetic activation significantly contributes to progression from compensated left ventricular hypertrophy to myocardial dysfunction through detrimental cardiac matrix remodeling. Besides, sympathetic overactivity achieved via β1AR overexpression (β1TG mouse) [87], [131] is accompanied by interstitial matrix remodeling and turnover by inducing MMP/TIMPs. In β1TG pro-collagen type-I and type-III mRNA and interstitial collagen protein expression are progressively increased from four-fold at 5 months to 17-fold at 12 months compared to 3 months of age. In β1TG mice at 5 months of age with compensated cardiac hypertrophy, an increased deposition of type-I and -III collagen fibers surrounding the cardiomyocytes is observed [131]. Contrariwise, the β1TG group at 12 months of age exhibits an asymmetrical distribution of the collagen fibers with disruption of the collagen network structure [132], [133]. A positive correlation between MMP-2 and noradrenaline in patients with heart failure has been demonstrated, also corroborated by in vitro experiments in human cardiac fibroblasts [134], supporting thereby the link between sympathetic stimulation and collagen turnover.
    Conclusion
    Contributors
    Conflict of interest
    Funding Dr. Gaetano Santulli, MD, PhD is supported by the National Institutes of Health (K99DK107895).
    Provenance and peer review