Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5

Abstract

Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced β-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic β-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsα or β-adrenergic receptors in transgenic mice results in enhanced cardiac function in young animals, but with prolonged overstimulation of this pathway, cardiomyopathy develops in these mice as they age. Similarly, chronic sympathomimetic amine therapy increases morbidity and mortality in patients with heart failure. Conversely, the use of β-blockade has proven to be of benefit and is currently part of the standard of care for heart failure. It is conceivable that interrupting distal mechanisms in the β-adrenergic receptor-G protein-adenylyl cyclase pathway may also provide targets for future therapeutic modalities for heart failure. Interestingly, there are two major isoforms of adenylyl cyclase (AC) in the heart (type 5 and type 6), which may exert opposite effects on the heart, i.e., cardiac overexpression of AC6 appears to be protective, whereas disruption of type 5 AC prolongs longevity and protects against cardiac stress. The goal of this review is to summarize the paradigm shift in the treatment of heart failure over the past 50 years from administering sympathomimetic amine agonists to administering β-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC.

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

“…PKA phosphorylates proteins in the heart which alter intracellular calcium handling and the calcium sensitivity of myofilaments (reviewed in Sharma and McNeill 2011). βAR activation also inhibits Raf activity, which activates MEK/ ERK signaling, thereby suppressing apoptosis in cardiomyocytes (Ho et al 2010).…”

“…The heart and brain are often regarded as the major targets of βAR signaling because they have the highest density of these receptors (Daly and McGrath 2011). Seventy to 80 % of the β1ARs and 20-30 % of the β2ARs in mammals are located in the heart (Reviewed in Ho et al 2010). Activation of these receptor subtypes in cardiomyocytes increases cardiac contractile force and contraction rate, increases conduction velocity and automaticity, and increases blood pressure (reviewed in Ho et al 2010;Taylor and Bristow 2004).…”

“…Seventy to 80 % of the β1ARs and 20-30 % of the β2ARs in mammals are located in the heart (Reviewed in Ho et al 2010). Activation of these receptor subtypes in cardiomyocytes increases cardiac contractile force and contraction rate, increases conduction velocity and automaticity, and increases blood pressure (reviewed in Ho et al 2010;Taylor and Bristow 2004). The receptors signal by increasing the activity of stimulatory guanine nucleotidebinding proteins (G proteins), thereby increasing the activity of PKA (Farfel et al 1999).…”

“…Sympathomimetic amines such as epinephrine, norepinephrine, and dopamine are agonists for the β-adrenergic receptors (βARs) (Johnson and Terrareceptor agonists increases mortality and morbidity in humans and other mammals (reviewed in Ho et al 2010). In humans, enhanced production of β2-adrenergic receptors resulting from specific genetic variants is inversely associated with life span (Zhao et al 2012).…”

The continuing saga of aging and heart failure

“…In that issue, a group of clinicianscientists discussed pertinent aspects of epidemiology and management of elderly patients with STEMI and HF [2,3]. Other expert clinician-scientists addressed, in the context of aging and HF, the role of inflammatory implications and fibrogenic pathways [4], autophagy [5], sarcoplasmic reticulum calcium signaling [6], stem cells [7], adiponectin [8], resveratrol and longevity [9], telomeres [10], osteopontin [11] and beta-adrenergic signaling [12].…”