Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from G s -dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby β-arrestins mediate β 1 AR signaling to the EGFR. This β-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via β-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.Introduction β-Adrenergic receptors (βARs) belong to the family of 7 transmembrane receptors (7TMRs) (1) and mediate the powerful regulatory effects on cardiac function of the catecholamine neurotransmitters epinephrine and norepinephrine. β 1 ARs constitute more than 70% of the cardiac βARs. Catecholamine stimulation of β 1 ARs results in activation of heterotrimeric G proteins followed by rapid phosphorylation of the receptor, resulting in desensitization (2). Homologous desensitization of β 1 ARs is brought about by phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs), leading to the recruitment of β-arrestin, which then sterically interdicts further coupling to G proteins (3) and targets the receptor for internalization (3). In addition to β-arrestin's role in terminating G protein signaling, recent studies demonstrate that β-arrestins also function as adapter molecules, allowing for the assembly of multiprotein signaling complexes such as ERKs and tyrosine kinases (4, 5). For the angiotensin II type 1A receptor (AT 1A R), this second wave of β-arrestin-mediated signaling has recently been demonstrated to be independent of G protein signaling (6) and to require the activity of GRKs 5 and 6 (7).The signaling mechanisms that underlie the activation of the mitogenic ERK growth response by 7TMRs are complex and likely result from both classical G protein-regulated effectors such as PKA and PKC and non-G protein-mediated crosstalk, such as EGFR transactivation (8). The current paradigm of transactivation involves agonist stimulation of a 7TMR, which through a number of undefined steps leads to MMP-mediated cleavage and

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Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.

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Given that in vivo telomere length reflects cellular turnover and exposure to oxidative and inflammatory damage, our data support accelerated aging in COPD.