Author + information
- Katie A. McCrink, PharmD,
- Jennifer Maning, DO,
- Angela Vu, DO,
- Malika Jafferjee, DO,
- Christine Marrero, DO,
- Ava Brill, PharmD,
- Ashley Bathgate-Siryk, PharmD,
- Samalia Dabul, PharmD,
- Walter J. Koch, PhD and
- Anastasios Lymperopoulos, PhD∗ ()
- ↵∗Neurohormonal Control of the Circulation Laboratory, Nova Southeastern University College of Pharmacy, 3200 South University Drive, HPD (Terry) Building/Room 1338, Fort Lauderdale, Florida 33328-2018
The 2 βarrestin isoforms, βarrestin1 and βarrestin2, normally decrease cardiac function and exacerbate post-myocardial infarction (MI) heart failure (HF) by desensitizing the procontractile G protein–dependent signaling of cardiac β1-adrenergic receptors (1). Although βarrestin1 exacerbates post-MI cardiac function and remodeling by diminishing cardiac adrenergic and inotropic reserves and by promoting apoptosis and inflammation, the βarrestin2 isoform may actually be beneficial post-MI (1).
Cardiac-specific βarrestin2 gene delivery at the time of MI improves cardiac function 3 weeks later (2). Additionally, post-MI adverse remodeling parameters (i.e., apoptosis, inflammation, and fibrosis) are all ameliorated (2), resulting in infarct size reduction (Figure 1A). The signaling mechanism for the direct increase in positive inotropy afforded by cardiac βarrestin2 is stimulation of SUMOylation of Sarco(Endo)plasmic Reticulum Ca2+-ATPase (SERCA2a), leading to enhanced levels and activity of this calcium pump (2,3). Notably, βarrestin1 lacks this effect on SERCA2a (2). Thus, cardiac-specific βarrestin2 gene transfer might be safely used for treatment of both acute and chronic HF, because it seems to act as a positive inotrope with beneficial, reverse remodeling effects in the failing heart.
Of note, however, βarrestin2 is virtually undetectable in human heart biopsies (Figure 1B); thus, βarrestin1, which mediates negative inotropy and adverse remodeling post-MI, is essentially the only βarrestin expressed in adult human hearts (1). This has 2 important implications. First, it may explain why the initially promising SERCA2a gene therapy failed in a recent large human HF trial (CUPID-2, NCT01643330). Apart from dosing and other design issues, the negative results of this trial may reflect the fact that simply restoring the levels of downregulated SERCA2a in the hearts of patients with HF is insufficient to confer clinical benefit; proper function of this calcium pump in the recipient hearts must also be ensured. In fact, SUMOylation of cardiac SERCA2a, necessary for its proper activity/function, is also deficient in patients with HF (3). Because βarrestin2 (but not βarrestin1) is a crucial inducer of cardiac SERCA2a SUMOylation (2) and the human heart almost exclusively expresses βarrestin1 (Figure 1B), it is entirely plausible that the virally delivered SERCA2a in the CUPID-2 trial was insufficiently SUMOylated and thus had subpar activity in the hearts of the recipient patients. In other words, human SERCA2a gene therapy must be coupled with cardiac βarrestin2 gene delivery (and probably also with SUMO1 gene delivery) to ensure proper SUMOylation and function of the delivered SERCA2a, thereby realizing its full therapeutic potential for human HF. Of course, given its virtual absence in normal healthy hearts and the likelihood of extracardiac side effects, rigorous clinical studies of βarrestin2 gene delivery alone are warranted to gauge the true risk-to-benefit ratio of human βarrestin2 gene therapy.
The other key clinical implication of our present findings pertains to the newly developed βarrestin-biased agonist drugs that target the angiotensin II type 1 receptor (AT1R), which also recently failed to show any benefit for acute HF treatment (BLAST-AHF, NCT01966601). Again, because the human heart mainly expresses βarrestin1, with very little (if any) βarrestin2 protein (Figure 1B), it follows then that these drugs actually stimulate βarrestin1, instead of βarrestin2, in patients with HF, which would have detrimental effects on cardiac inotropy in the acute HF setting (1). Therefore, these drugs might also need to be combined with cardiac βarrestin2 gene therapy to attain therapeutic benefit for human HF.
In summary, our present study aims to bring the attention of clinicians and pharmacologists to the remarkable functional divergence of the 2 βarrestins in the heart, which, coupled with the virtual absence of the “good” cardiac βarrestin2 protein in humans, highlights potential causes of 2 recent clinical failures of novel, otherwise promising therapies for human HF. Importantly, it points to a “missing link” (boosting endogenous cardiac βarrestin2 levels) for these therapeutics that is necessary to attain efficacy for human HF treatment.
Please note: This study was supported in part by an American Heart Association Scientist Development Grant (#09SDG2010138, National Center) and a Nova Southeastern University’s President’s Faculty Research & Development Grant (both to Dr. Lymperopoulos). Dr. McCrink was supported by an American Foundation for Pharmaceutical Education Research Scholarship. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation