Abstract
Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12–16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.
Highlights
The prevalence of heart failure (HF) is expected to increase due to the older population continuously growing (Virani et al, 2021)
We used echocardiography to study the effects of β-arrestin-2 deletion on cardiac function in young (3–6 months) and aged (12–16 months) wild-type equivalent (WT) and KO mice
We propose a novel concept that β-arrestin-2 signaling is essential for normal aging
Summary
The prevalence of heart failure (HF) is expected to increase due to the older population continuously growing (Virani et al, 2021). Over activation of AT1R by ang II has been implicated in the development β-arrestin-2 Protects Aging Hearts of hypertension during aging (Mattson and Maudsley, 2009). Previous studies demonstrated that β-arrestin biased ligands, that selectively block ang II binding to AT1R, simultaneously activate β-arrestin signaling pathways (Whalen et al, 2011; Wisler et al, 2014). Our laboratory reported that promotion of β-arrestin-2 signaling via the action of biased ligands at the AT1R was able to reverse these maladaptive changes in a genetic model of heart failure with dilated cardiomyopathy (DCM; Ryba et al, 2017). We found that biased agonism of AT1R in chronic ang II infusion in rats preserved myofilament Ca2+ responsiveness and prevented ang II-related maladaptation (Monasky et al, 2013). A role for β-arrestin-2 signaling in aged-related HF remains unknown
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