Author + information
- aCedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
- bDepartment of Medicine, UCLA, Los Angeles, California
- ↵∗Address for correspondence:
Dr. Robin M. Shaw, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, 1016 Plaza Level, Davis Building, Los Angeles, California 90048.
Myocardial hypertrophy can be a readily available biomarker of maladaptive cardiac remodeling. It is an important milestone in the continuum of heart failure development and manifests as an increased myocardial mass and altered mechanics of diastolic relaxation on echocardiography. Importantly, however, pathological myocardial hypertrophy constitutes an entire reprogramming of the cardiomyocytes’ metabolic, energetic, and biomolecular profile that occurs in the setting of a general proinflammatory, profibrotic milieu. Studies have shown that left ventricular (LV) hypertrophy (LVH) is a predictor of adverse cardiovascular events, such as arrhythmias, heart failure, and even sudden cardiac death (1). The heterogeneity of pathological stimuli that trigger the development of LVH poses challenges in characterizing this condition as a single pathological entity as well as finding novel therapeutic targets. Not surprisingly, there is a paucity of therapeutic options that change the course of the disease in patients with heart failure and especially for patients with heart failure with preserved ejection fraction.
Calcineurin, a Ca2+ sensor in the cytoplasm of the cardiomyocyte, is a serine/threonine phosphatase that is regulated through the adaptor protein calmodulin. In the canonical calcineurin pathway, a cardiac specific isoform CnAβ2 acts on nuclear factor of activated T cells (NFAT). NFAT dephosphorylation allows its nuclear translocation and transcriptional activation of pro-hypertrophy genes. For instance, deletion of the inhibitory domain of CnAβ2 leads to constitutive activation of the NFAT pathway and induction of cardiac hypertrophy (2). Furthermore, constitutively activated calcineurin or NFAT also replicates the hypertrophic response (3). Although there have been hints that calcineurin inhibition is not universally beneficial (4), the conventional wisdom is that calcineurin is essential for pathological, but not physiological hypertrophy development (5).
In this light, Padrón-Barthe et al. (6) now report in this issue of the Journal the surprising finding that an alternatively spliced noncanonical isoform of calcineurin, namely CnAβ1, exists in the heart and has a protective role in myocardium. This study is a natural extension of the authors’ prior findings that CnAβ1 is induced by insulin-like growth factor (IGF-1) and conveys a protective and regenerative role in skeletal muscle (7). In the present study, the authors used a genetic mouse model with cardiac-specific expression of the human CnAβ1 isoform under the control of the alpha myosin heavy chain promoter (αMHC-CnAβ1). In the transgenic mice, CnAβ1 overexpression led to attenuation of the hypertrophic response as well as a decrease in interstitial and perivascular fibrosis in response to transaortic constriction (TAC)-induced afterload increase. This protective response by CnAβ1 overexpression is not mediated by interfering with NFAT signaling, as evidenced by similar TAC-induced NFAT increase in both the transgenic and WT mice (6).
To understand the link between CnAβ1 overexpression and decreased hypertrophy, the authors performed comprehensive transcriptional and translational profiling of myocardial samples from the αMHC-CnAβ1 genetic model. They found significant up-regulation of cascades involved in serine and one-carbon metabolism that were partially dependent on mTOR/Akt/ATF4 signaling. This study is the first to identify (and validate) serine and one-carbon pathways in cardiac function and remodeling. These metabolic pathways are major suppliers of NADH and NADPH, which are essential substrates that fuel the mitochondrial electron transport chain, energy production through oxidative phosphorylation, as well as other important anabolic pathways and antioxidant responses (8). Prior studies have shown that in LVH, there is an important metabolic switch leading to an energy-deficient and catabolic state characterized by mitochondrial fragmentation and injury, energetics microdomain disorganization, and increased oxidative stress (8).
To confirm the role of endogenous CnAβ1, Padrón-Barthe et al. (6) also deleted intron 12-13 within the CnAβ1 unique C-terminus domain, thus effectively knocking out CnAβ1 activity while preserving CnAβ2 expression. This new genetic mouse model, CnAβ1△i12, exhibits spontaneous hypertrophy by 15 months of age and ultimately pump failure even in the absence of afterload increase. When subjected to TAC, the transgenic mice developed greater degree of hypertrophy and a decreased expression of serine and one-carbon metabolites, consistent with the proposed role of CnAβ1 in these metabolic pathways (6). It should be noted that when subjected to TAC-induced pressure overload, the CnAβ1△i12 mice took longer for LV systolic function to decline. The authors postulate that the greater degree of myocardial hypertrophy in the CnAβ1△i12 mice might be delaying the transition to systolic dysfunction.
In the future the timing of the transition from hypertrophy to LV ejection fraction decline needs to be fully explored. It should also be mentioned that the findings in this study provide a starting point for more detailed exploration of CnAβ1 biology. The transcriptional profiling and proteomics performed were exhaustive, but remain primarily correlative. Most any biochemical change that affects cardiomyocyte hypertrophy, cardiac fibrosis and overall function will likely be reflected as altered mitochondrial function as well (9). Furthermore, blocking the mTOR pathway with rapamycin blunted the effect of CnAβ1 overexpression, but did not fully inhibit it (6). These issues do not detract from the surprising and major finding of Padrón-Barthe that a calcineurin pathway is protective to myocardium, and is mediated by serine and one-carbon activation (6). This work should compel many investigators to now explore in detail the role of CnAβ1 in maintaining normal physiological function and also in ameliorating a pathological hypertrophic response to stress.
The study by Padrón-Barthe et al. (6) is an important advance in understanding the mechanisms for the metabolic and energetics switch that occurs in maladaptive myocardial hypertrophy. The authors demonstrate for the first time that the unique calcineurin splice variant CnAβ1 plays a novel and counterintuitive noncanonical role in the heart by activating cardioprotective pathways involved in serine and one-carbon metabolism along with up-regulation of antioxidant enzymes that enhance mitochondrial function. We congratulate the authors for opening a new window into the pathogenesis of myocardial remodeling, and new opportunities for therapeutic solutions.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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