Modulation of beta-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 beta-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic beta-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsalpha or beta-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 beta-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 beta-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 beta-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC.

Fig. 1. Schematic representation of β-AR signaling pathway in cardiac myocytes

Upon β-AR stimulation, the Gsα subunit-bound AC produces cAMP which activates target molecules, PKA and Epac. PKA regulates Ca²⁺ homeostasis through SR and LTCC, increases contractility. Under conditions of excessive sympathetic stimulation, PKA-induced Ca²⁺ leads to hypertrophy. On the other hand, activated PKA inhibits Raf, which results in the activation of the MEK/ERK signaling, and thus suppression of apoptosis. In contrast, Epac, the other target protein of cAMP than PKA, induces myocyte apoptosis via the P38MAPK pathway. Upon activation of β₂-AR, the Giβγ subunits are released and activate the PI3K/Akt pathway. Activated Akt inhibits apoptosis, and accelerates hypertrophy

Fig. 2. Effects of cardiac overexpression of β₁-AR, β₂-AR or Gsα in mice on development of cardiomyopathy

Panel a. The ages at 50% mortality in Tg mice with overexpression of β₁-AR (blue bar, unpublished results), β₂-AR (green bar) [101] or Gsα (red bar) [98] are shown in panel compared against wild type (WT) (FVB [204], or C57 [203]). The time to 50% mortality for the transgenic mice was less than half of that for the respective WT mice (*, p<0.05 compared to WT). Panel b. Decreased LV ejection fraction (LVEF) in the Tg animals vs WT [98,119]. Panel c. Cardiac fibrosis was increased in the Tg animals as compared to WT animals [98,119]. Panel d. Increased cardiac apoptosis in the Tg animals. The percent apoptotic cells in the transgenic mice were normalized against WT [99,119] (*, p<0.05 compared to WT). Figures used and modified with permission

Fig. 3. β-blockade increases survival, and preserves cardiac function in heart failure patients and Gsα Tg mice

Panel a. Kaplan-Meier survival curve showing mortality improvement in survival in heart failure patients on carvedilol (red line) vs placebo patients (blue line) [131] and Gsα Tg mice treated with propranolol (solid black line) vs vehicle (broken line) [98] indicating prolongation of lifespan with β-blockade. Panel b. β-blockade (blue bars) also resulted in improvement in LV function in heart failure patients [132] and Gsα Tg mice [98] as indicated by improved LVEF (*, p<0.05 vs placebo vs vehicle). Figures used and modified with permission

Fig. 4. AC5KO in mice protects against the development of cardiomyopathy

AC5KO (yellow bar) enhances protection against heart failure induced by pressure overload [159] or catecholamine stress (chronic isoproterenol) [160]. Preserved LVEF (Panel a) and reduced cardiomyocyte apoptosis (Panel b) was observed in AC5KO mice compared with WT in response to catecholamine stress (*, p<0.05 compared to no treatment, gray bar) [160]. Figures used and modified with permission

Fig. 5. Disruption of AC5 in mice protects against aging cardiomyopathy

Kaplan-Meier survival curve for AC5KO (yellow square) shows prolonged life span compared with WT (open square), accompanied by preservation of LVEF (left in inset) and a reduction in myocardial apoptosis (right in inset) in the older mice. *, p<0.05 vs WT. [179]. Figures used and modified with permission

Fig. 6. Mechanism of AC5-mediated regulation of longevity

Disruption of AC5 activates the MEK/ERK signaling pathway [179]. The activation of ERK leads to increased expression of manganese superoxide dismutase (MnSOD), which results in inhibition of apoptosis. On the other hand, the ERK signaling activates the cell survival signaling (ref). Taken together, these mechanisms contribute to increased longevity in AC5KO mice. Western blots demonstrate the changes of key enzymes in the heart by disruption of AC5 [179]. Figures used and modified with permission