β 2 -Adrenergic Signaling Switches from Cardioprotective to Cardiotoxic in Acute vs. Chronic Oxidative Stress

ABSTRACT BACKGROUND AND PURPOSE β-adrenergic receptors (AR) regulate both cardiac function and remodeling. Many studies suggest that, in addition to their effects on heart rate and contractility, β 1 -ARs mediate cardiotoxic signaling, whereas β 2 -ARs are generally cardioprotective. However, there is conflicting data on the role of β 2 -ARs, differing dependent on the nature of the stress. Given the extremely common use of β-blockers and agonists clinically, we sought to understand the differential cardioprotective/cardiotoxic effects of β 2 -AR signaling dependent on timing (acute vs. chronic) and type of cardiotoxic stress. EXPERIMENTAL APPROACH Wild-type (WT) and β-AR knockout (β 1 -KO and β 2 -KO) mice were subjected to acute (15 mg·kg -1 x 1 dose) or chronic (2 mg·kg -1 ·wk -1 x 7 wks) oxidative stress using doxorubicin (DOX). Survival, cardiac function and histopathology were assessed and differential signaling activation determined by Western blot and gene expression by RNA-seq. KEY RESULTS We have shown that β 2 -KOs manifest extreme cardiotoxicity with acute DOX (100% mortality within 30 min), supporting a strong cardioprotective role of β 2 -signaling. In marked contrast, with chronic DOX, β 2 -KO had enhanced survival (t½ 54 d vs. 42 d in WT) and attenuated cardiac dysfunction. In β 2 -KO, acute DOX activated stress MAPKs (p38, ERK and JNK), whereas chronic DOX did not; furthermore, in the absence of β2-ARs, oxidative stress and lipid accumulation were reduced, genes regulating compensatory metabolic pathways (AMPK and insulin/PI3K) were upregulated, and genes regulating mitochondrial and contractile function were preserved, whereas they were downregulated in WT with chronic DOX. CONCLUSIONS β 2 -AR signaling switches from being cardioprotective during acute oxidative stress, to cardiotoxic during chronic stress. Inhibition of β 2 -AR signaling during chronic stress induces signaling and metabolic compensations that serve to reduce oxidative injury. This unexpected temporal switching has potential significant implications for all models of cardiovascular disease, as well as for the clinical use of subtype-specific β-blockers. CLINICAL PERSPECTIVE What is new? Our finding that β2-adrenergic receptor signaling can switch from being beneficial (cardioprotective) to detrimental (cardiotoxic) depending on the acuteness or chronicity of a cardiac stressor. Identification of the mechanisms by which this temporal switch is mediated could lead to new drug development. What are the clinical implications? Our findings provide potential guidance in choosing between a β1-specific vs. a β1/2-non-specific drug when treating specific cardiovascular diseases based on their temporal characteristics. The temporal protective/toxic switching that we describe could be a mechanism common to many other drugs, yet is rarely tested, suggesting the need for additional studies using temporal course as a factor.