Disruption of type 5 adenylyl cyclase prevents β-adrenergic receptor cardiomyopathy: A novel approach to β-adrenergic receptor blockade

Abstract

Yan L, Vatner SF, Vatner DE. Disruption of type 5 adenylyl cyclase prevents ␤-adrenergic receptor cardiomyopathy: A novel approach to ␤-adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 307: H1521-H1528, 2014. First published September 5, 2014; doi:10.1152/ajpheart.00491.2014.-␤-Adrenergic receptor (␤-AR) blockade is widely used to treat heart failure, since the adverse effects of chronic ␤-AR stimulation are central to the pathogenesis of this disease state. Transgenic (Tg) mice, where ␤-AR signaling is chronically enhanced by overexpression of cardiac ␤ 2-ARs, is a surrogate for this mechanism, since these mice develop cardiomyopathy as reflected by reduced left ventricular (LV) function, increased fibrosis, apoptosis, and myocyte hypertrophy. We hypothesized that disruption of type 5 adenylyl cyclase (AC5), which is in the ␤-AR signaling pathway in the heart, but exerts only a minor ␤-AR blocking effect, could prevent the cardiomyopathy in ␤2-AR Tg mice without the negative effects of full ␤-AR blockade. Accordingly, we mated ␤2-AR Tg mice with AC5 knockout (KO) mice. The ␤2-AR Tg ϫ AC5 KO bigenic mice prevented the cardiomyopathy as reflected by improved LV ejection fraction, reduced apoptosis, fibrosis, and myocyte size and preserved exercise capacity. The rescue was not simply due to a ␤-blocking effect of AC5 KO, since neither baseline LV function nor the response to isoproterenol was diminished substantially compared with the negative inotropic effects of ␤-blockade. However, AC5 disruption in ␤2-AR Tg activates the antioxidant, manganese superoxide dismutase, an important mechanism protecting the heart from cardiomyopathy. These results indicate that disruption of AC5 prevents the cardiomyopathy induced by chronically enhanced ␤-AR signaling in mice with overexpressed ␤2-AR, potentially by enhancing resistance to oxidative stress and apoptosis, suggesting a novel, alternative approach to ␤-AR blockade.

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

“…14,15 We observed reduction of left ventricular mass following ERT in GAA-KO mice (Figure 1D), and the ratio of left ventricle mass to body weight was reduced to approximately 3.8, which is comparable to 3.0–3.5 of healthy mice. 16,17 However, propranolol administration prevented any reduction of left ventricular mass, in comparison with untreated GAA-KO mice (Figure 1D). The reduction of ventricular mass by ERT in Pompe mice was generalized, and not limited to the left ventricle, because the ratio of left ventricle mass to total ventricular mass was not changed by ERT, in comparison with untreated GAA-KO mice (not shown).…”

Inhibition of Adenylyl Cyclase Type 5 Increases Longevity and Healthful Aging through Oxidative Stress Protection

“…There is accumulating evidence that increased oxidative stress is involved in the pathogenesis of various types of cardiomyopathy [ 88 ], including dilated [ 89 , 90 ], diabetic [ 91 , 92 ], ischemic [ 93 , 94 ], hypertensive [ 95 ], adriamycin-induced [ 96 ], and pressure overload-induced cardiomyopathy [ 97 – 99 ], as well as beta adrenergic receptor overexpression induced cardiomyopathy [ 3 , 100 ]. It is important to note that oxidative stress affects different cell types involved in cardiomyopathy, not just cardiac myocytes.…”

“…The AC5 KO model is also protected against cardiomyopathy and heart failure through oxidative stress mechanisms [ 3 ] (Figures 3 – 5 ). For example, chronic beta adrenergic receptor ( β -AR) stimulation induces cardiomyopathy and heart failure by increasing markers of oxidative stress damage including myocyte necrosis and apoptosis [ 100 ]. We found that augmenting oxidative stress by mating the AC5 KO mice with MnSOD KO mice resulted in loss of the protection against the decreased cardiac function and increased cardiac fibrosis in response to chronic catecholamine stimulation in the double knockouts ( Figure 5 ) [ 3 , 5 ].…”

“…In this model mating the AC5 Tg mice with MnSOD Tg mice rescues the cardiomyopathy ( Figure 5 ). Furthermore, AC5 KO can also prevent the cardiomyopathy induced by chronically enhanced β -AR signaling in mice with overexpressed β 2-AR also, potentially, through enhancing resistance to oxidative stress [ 100 ]. These findings confirm the importance of oxidative stress in the pathogenesis of heart failure in general and in the protection afforded by the AC5 KO model in particular.…”

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

“…However, the overwhelming preponderance of data in patients support the concept that exercise improves not only healthy lifespan, but also longevity, as it clearly is protective against cardiovascular disease, diabetes, and obesity, all of which are known to reduce lifespan. As the AC5 KO mice exhibit longevity and protection against diabetes, obesity, and cardiovascular disease (Yan et al ., 2007, 2014; Lai et al ., 2013; Ho et al ., 2015) along with enhanced exercise performance demonstrated in the current investigation, this model replicates the human paradigm of healthful aging. Conversely, enhanced β adrenergic signaling results in diminished lifespan, not only in transgenic animal models, for example, overexpression of Gsα (Iwase et al ., 1996, 1997), but also in human aging studies with increased β2 adrenergic receptor genotype, where longevity is diminished (Zhao et al ., 2012).…”