Junctophilin-2 at the intersection of arrhythmia and pathologic cardiac remodeling

Cardiomyopathy represents a spectrum of primary myocar-dial diseases with a diverse array of clinical manifestations. The majority of cardiomyopathies represent myocardial diseases secondary to heritable genetic defects, such as sarcomeric mutations associated with hypertrophic cardiomyopathy. A relatively unexplored type of cardiomyopathic remodeling is secondary to electrical abnormalities. Premature ventricular contractions (PVCs), or early spontaneous depolarizations of the ventricular myocardium, are common in the general population and can occur in the absence of structural or arrhythmic heart disease. While as much as 4%–5% of the population demonstrates PVCs, a relatively small number of individuals will carry a PVC burden that is sufficient for the development of impaired systolic function and ventricular dilation.¹ This so-called PVC-induced cardiomyopathy represents a mechanism by which dyssynchro-nous electrical activation of the heart progressed to pathologic remodeling. In this issue of HeartRhythm, Jiang et al² use a canine model to explore the link between PVCs and the development of heart failure. This study provides some interesting novel mechanistic insights into the mechanisms underlying Ca handling in the heart.

Proper cardiac contractility requires efficient communication between membrane depolarization and mechanical myofilament contraction, which is mediated by intracellular Ca signaling. During this process, known as excitation-contraction coupling, Ca enters cardiomyocytes through the voltage-gated L-type Ca channel (Cav1.2) located along protrusions of the plasma membrane known as transverse (T) tubules. Efficient Ca signaling occurs at the cardiac dyads: junctions between the T tubules and cell’s internal Ca stores known as the sarcoplasmic reticulum (SR). Ca influx via Cav1.2 channels activates ryanodine receptor type 2 (RyR2) to induce a greater SR Ca release. The ensuing increase in cytosolic Ca levels triggers contraction of the cardiac sarcomere, which subsequently relaxes upon Ca sequestration to the SR via the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) and by Ca extrusion from the cell by the sodium-calcium exchanger.

Dyads are held together by junctophilin-2 (JPH2), which is necessary for efficient excitation-contraction coupling.³ JPH2 dysregulation has been implicated in both hypertrophic and dilated cardiomyopathy in humans and in rodent models of disease. In this article, Jiang et al² identify an association between canine PVC-induced cardiomyopathy and loss of JPH2 expression with derangement in T-tubule ultrastruc-ture. This work builds on initial observations that loss of JPH2 in mouse hearts leads to T-tubule disruption and subsequent cardiomyopathy owing to inefficient Ca signaling.⁴ Additional studies have demonstrated that missense mutations in JPH2 have been discovered in patients with hypertrophic cardiomyopathy⁵ and expression silencing of JPH2 induces loss of ventricular ejection fraction in mice. Isolated ventricular myocytes from these JPH2 knockdown mice demonstrated impaired excitation-contraction coupling and inefficient intracellular Ca signaling with mislocaliza-tion of RyR2 and Cav1.2.⁶ In this way, Ca dysregulation and JPH2 expression are central to maintaining the critical cardiomyocyte ultrastructure needed for contractile efficiency.

The vast majority of mechanistic insights into JPH2 disease pathogenesis, and cardiomyopathy as a whole, have been gleaned from rodent models, and there is a paucity of studies using larger mammalian models, which may correlate more closely with human disease. Huizar et al⁷ developed a canine model in which pacing-induced PVCs led to temporary left ventricular dysfunction. This model was used to demonstrate a loss of JPH2 expression associated with impaired excitation-contraction coupling and decreased systolic function in PVC-induced cardiomyopathy.⁸ Jiang et al² expand on this work by highlighting the role of JPH2 as a central player in the mechanism of PVC-induced cardiomyopathy, in which several dyadic proteins including Cav1.2 and JPH2 are downregulated. The authors delve further into the downstream consequences of JPH2 loss by performing a co-immunoprecipitation screening of JPH2 with various dyadic proteins including Ca handling, scaffolding, and ion channel proteins. Two of the major interactors with JPH2 were found to be ion channels, one of which was Cav1.2.

Jiang et al² highlight the unique regulatory role that JPH2 has in cardiac ion channels. They demonstrated that JPH2 positively regulates Cav1.2 when overexpressed in HEK293 cells. Since HEK cells do not have dyadic structures, further studies are warranted to determine whether a similar regulatory structure between JPH2 and Cav1.2 exists in cardiomyocytes isolated from dogs with PVC-induced cardiomyopathy. Even so, this is the first indication that JPH2 regulates Cav1.2, which supports the idea that JPH2 is much more than a structural protein but indeed regulates ion channel function. This builds on previous work, which demonstrated that JPH2 negatively regulates RyR2.⁵ The present finding that JPH2 positively regulates Cav1.2 broadens our perspective on JPH2, highlighting its importance in multiple aspects of excitation-contraction coupling. In this way, the authors advance our understanding of JPH2 at both a molecular and a physiological level.

PVC-induced cardiomyopathy represents the intersection between arrhythmia and cardiomyopathy. It is clear that JPH2, which has been implicated in both primary cardiac diseases such as heart failure and hypertrophic cardiomyopathy as well as arrhythmogenesis, is at the center of this emerging model. With this new level of understanding along with the correlation of JPH2 mutation with disease in humans, JPH2 may be an important target for therapeutic intervention in several cardiomyopathies.