Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II

Zhu, Wuqiang; Wang, Shiqiang; Chakir, Khalid; Yang, Dongmei; Zhang, Tong; Brown, Joan Heller; Devic, Eric; Kobilka, Brian K.; Cheng, Heping; Xiao, Rui‐Ping

doi:10.1172/jci16326

Cited by 244 publications

(266 citation statements)

References 50 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…Previously, cAMP/PKA was thought to play a role in the β 1 -adrenergically induced myocyte apoptosis (22). However, evidence now exists that the β 1 -adrenergically induced myocyte apoptosis is not PKA dependent (23). Instead, the cardiac effects of sustained β 1 -adrenergic stimulation are associated with a cAMP-independent increase of intracellular Ca 2+ and activation of CaMKII (24).…”

Section: Discussionmentioning

confidence: 99%

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Mao

Iwai

Fukuoka

et al. 2008

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Auto-antibodies against the β 1 -adrenoceptors are present in 30−40% of patients with dilated cardiomyopathy. Recently, a synthetic peptide corresponding to a sequence of the second extracellular loop of the human β 1 -adrenoceptor (β 1 -EC II ) has been shown to produce endoplasmic reticulum (ER) stress, myocyte apoptosis and cardiomyopathy in immunized rabbits. To study the direct cardiac effects of anti-β 1 -EC II antibody in intact animals and if they are mediated via β 1 -adrenoceptor stimulation, we administered IgG purified from β 1 -EC II -immunized rabbits to recombination activating gene 2 knock-out (Rag2 −/− ) mice every two weeks with and without metoprolol treatment. Serial echocardiography and cardiac catheterization showed that β 1 -EC II IgG reduced cardiac systolic function after 3 months. This was associated with increase in heart weight, myocyte apoptosis, activation of caspase-3, -9 and -12, and increased ER stress as evidenced by upregulation of GRP78 and CHOP and cleavage of ATF6. The Rag2 −/− mice also exhibited increased phosphorylation of CaMKII and p38 MAPK. Metoprolol administration, which attenuated the phosphorylation of CaMKII and p38 MAPK, reduced the ER stress, caspase activation and cell death. Finally, we employed the small-interfering RNA technology to reduce caspase-12 in cultured rat cardiomyocytes. This reduced not only the increase of cleaved caspase-12 but also of the number of myocyte apoptosis produced by β 1 -EC II IgG. Thus, we conclude that ER stress plays an important role in cell death and cardiac dysfunction in β 1 -EC II IgG cardiomyopathy, and the effects of β 1 -EC II IgG are mediated via the β 1 -adrenergic receptor.

show abstract

Section: Discussionmentioning

confidence: 99%

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Mao

Iwai

Fukuoka

et al. 2008

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…10,11,22 The underlying mechanisms have been suggested to involve the reactive oxygen species (ROS)/JNK-dependent mitochondrial pathway 11 and the Ca 2ϩ -activated calmodulin kinase II pathway. 28,29 Recent studies have also shown that ␤-adrenergic stimulation activates p38 MAPK, which provides a negative feedback to ISO-induced contractile response in cardiomyocytes; and cardiac overexpression of p38 MAPK results in cardiac remodeling and severe cardiomyopathy. 30,31 The current study provides additional insights and identifies ASK1, upstream of JNK/p38, as a mediator of the detrimental effects elicited by enhanced ␤-agonist stimulation.…”

Section: Discussionmentioning

confidence: 99%

Small Heat-Shock Protein Hsp20 Attenuates β-Agonist–Mediated Cardiac Remodeling Through Apoptosis Signal–Regulating Kinase 1

Fan

Yuan

Song

et al. 2006

Circulation Research

View full text Add to dashboard Cite

Abstract-Chronic stimulation of the ␤-adrenergic neurohormonal axis contributes to the progression of heart failure and mortality in animal models and human patients. In cardiomyocytes, activation of the ␤-adrenergic pathway has been shown to result in transiently increased expression of a cardiac small heat-shock protein Hsp20. The present study shows that cardiac overexpression (10-fold) of Hsp20 may protect the heart against ␤-agonist-induced cardiac remodeling, associated with isoproterenol (50 g/g per day) infusion for 14 days. Hsp20 attenuated the cardiac hypertrophic response, markedly reduced interstitial fibrosis, and decreased apoptosis. Contractility was also preserved in hearts with increased Hsp20 levels. These beneficial effects were associated with attenuation of the ASK1-JNK/p38 (apoptosis signal-regulating kinase 1/c-Jun NH 2 -terminal kinase/p38) signaling cascade triggered by isoproterenol, whereas there was no difference in either extracellular signal-related kinase 1/2 or Akt activation. Parallel in vitro experiments supported the inhibitory role of Hsp20 on enforced ASK1-JNK/p38 activation in both H9c2 cells and adult rat cardiomyocytes. Immunostaining studies also demonstrated that Hsp20 colocalizes with ASK1 in cardiomyocytes. Taken together, our findings indicate that (1) ␤-agonist-induced cardiac injury is associated with activation of the ASK1-JNK/p38 cascade; (2) increased expression of Hsp20 attenuates the induction of remodeling, dysfunction, and apoptosis in response to sustained ␤-adrenergic stimulation; and (3) A poptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAPKKK), which activates the c-Jun NH 2 -terminal kinase (JNK) (also known as stress-activated protein kinase [SAPK]) and p38 MAPK signaling cascades. 1 Overexpression of wild-type (WT) or constitutively active ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas rat neonatal ASK1-deficient cardiomyocytes were resistant to H 2 O 2 -induced apoptosis. 2 Recent studies have indicated that ablation of ASK1 was associated with (1) inhibition of angiotensin II-and G protein-coupled receptor (GPCR) agonist-induced heart dysfunction and dilatation 3,4 ; (2) attenuation of cardiac remodeling mediated by myocardial infarction and pressure overload 2 ; and (3) rescue of Raf-1 knockout-induced cardiac dysfunction and apoptosis. 5 These observations suggest that inhibition of ASK1 may be a promising target for prevention of cardiac remodeling and, thus, suppression of heart failure onset and progression.Heart failure is characterized by enhanced adrenergic stimulation to correct systolic and diastolic dysfunction, but chronic elevation of sympathetic drive can exert deleterious effects on the myocardium, promoting the development of fibrotic cardiomyopathy. 6,7 The mechanisms underlying the transition between the contractile benefits and the maladaptive processing, including cell death, are still heavily debated. 8,9 The MAPKs, mainly incl...

show abstract

“…β-Blockers are commonly prescribed pharmaceuticals used in the treatment of CHF (1,2). It is believed that β-blockers act to inhibit pathogenic βAR signaling pathways, including those mediating cell death (31)(32)(33). As G-protein-dependent signaling has been attributed to cardiomyocyte death, the use of a β-arrestin-biased agonist could be an advantageous therapeutic approach (34).…”

Section: Icl1-9mentioning

confidence: 99%

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

Carr

Schilling

Song

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

β-adrenergic receptors (βARs) are critical regulators of acute cardiovascular physiology. In response to elevated catecholamine stimulation during development of congestive heart failure (CHF), chronic activation of G s -dependent β 1 AR and G i -dependent β 2 AR pathways leads to enhanced cardiomyocyte death, reduced β 1 AR expression, and decreased inotropic reserve. β-blockers act to block excessive catecholamine stimulation of βARs to decrease cellular apoptotic signaling and normalize β 1 AR expression and inotropy. Whereas these actions reduce cardiac remodeling and mortality outcomes, the effects are not sustained. Converse to G-protein-dependent signaling, β-arrestin-dependent signaling promotes cardiomyocyte survival. Given that β 2 AR expression is unaltered in CHF, a β-arrestin-biased agonist that operates through the β 2 AR represents a potentially useful therapeutic approach. Carvedilol, a currently prescribed nonselective β-blocker, has been classified as a β-arrestin-biased agonist that can inhibit basal signaling from βARs and also stimulate cell survival signaling pathways. To understand the relative contribution of β-arrestin bias to the efficacy of select β-blockers, a specific β-arrestin-biased pepducin for the β 2 AR, intracellular loop (ICL)1-9, was used to decouple β-arrestin-biased signaling from occupation of the orthosteric ligand-binding pocket. With similar efficacy to carvedilol, ICL1-9 was able to promote β 2 AR phosphorylation, β-arrestin recruitment, β 2 AR internalization, and β-arrestin-biased signaling. Interestingly, ICL1-9 was also able to induce β 2 AR-and β-arrestin-dependent and Ca 2+ -independent contractility in primary adult murine cardiomyocytes, whereas carvedilol had no efficacy. Thus, ICL1-9 is an effective tool to access a pharmacological profile stimulating cardioprotective signaling and inotropic effects through the β 2 AR and serves as a model for the next generation of cardiovascular drug development.B eta-antagonists, also known as β-blockers, have been indicated for the treatment of pathological cardiac diseases, including congestive heart failure (CHF) and high blood pressure, for decades (1, 2). A select number of these agents, including the clinically used carvedilol, have been identified as β-arrestinbiased agonists of β-adrenergic receptors based on their ability to promote β-arrestin-dependent signaling over G-protein activation (3, 4). It is believed that the β-arrestin activation may provide additional cardioprotection based on its ability to mediate antiapoptotic signaling. As these are orthosteric ligands, there have been no means to decouple the activation of receptor-dependent β-arrestin signaling from the occupation of the orthosteric ligandbinding pocket to study their independent contribution to its efficacy as these properties appear inherently linked.Recently, we described the characterization of a library of modulators of the β 2 -adrenergic receptor (β 2 AR) known as pepducins (5). Pepducins are lipidated peptides derived from the intracel...

show abstract

Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II

Cited by 244 publications

References 50 publications

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Small Heat-Shock Protein Hsp20 Attenuates β-Agonist–Mediated Cardiac Remodeling Through Apoptosis Signal–Regulating Kinase 1

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction

Contact Info

Product

Resources

About

Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II

Cited by 244 publications

References 50 publications

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Adoptive passive transfer of rabbit β1-adrenoceptor peptide immune cardiomyopathy into the Rag2−/− mouse: Participation of the ER stress

Small Heat-Shock Protein Hsp20 Attenuates β-Agonist–Mediated Cardiac Remodeling Through Apoptosis Signal–Regulating Kinase 1

β-arrestin–biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction

Contact Info

Product

Resources

About

β-arrestin–biased signaling through the β ₂ -adrenergic receptor promotes cardiomyocyte contraction