Junctophilin-2 Expression Silencing Causes Cardiocyte Hypertrophy and Abnormal Intracellular Calcium-Handling

Abstract

Background-Junctophilin-2 (JPH2), a protein expressed in the junctional membrane complex, is necessary for proper intracellular calcium (Ca 2ϩ ) signaling in cardiac myocytes. Downregulation of JPH2 expression in a model of cardiac hypertrophy was recently associated with defective coupling between plasmalemmal L-type Ca 2ϩ channels and sarcoplasmic reticular ryanodine receptors. However, it remains unclear whether JPH2 expression is altered in patients with hypertrophic cardiomyopathy (HCM). In addition, the effects of downregulation of JPH2 expression on intracellular Ca 2ϩ handling are presently poorly understood. We sought to determine whether loss of JPH2 expression is noted among patients with HCM and whether expression silencing might perturb Ca 2ϩ handling in a prohypertrophic manner. Methods and Results-JPH2 expression was reduced in flash-frozen human cardiac tissue procured from patients with HCM compared with ostensibly healthy traumatic death victims. Partial silencing of JPH2 expression in HL-1 cells by a small interfering RNA probe targeted to murine JPH2 mRNA (shJPH2) resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy. Whereas expression levels of major Ca

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…We propose that increases in JPH2 and improvements in t‐tubule morphology mediate the augmented RV function, which is further supported by the significant relationships between JPH2 and RV function (Figure 5). These results agree with several studies showing that reduced levels of JPH2 are associated with left ventricular dysfunction in animal models36, 37, 38, 39, 40 and human disease states15, 41 and that increased expression of JPH2, achieved via transgenic overexpression,19 antagonism of miR‐24,42 viral‐mediated overexpression,20 or inhibition of calpain proteases,43 improves cardiac function in animal models of LV dysfunction. Thus, increased JPH2 likely mediates the improved RV‐PA coupling in MCT‐colchicine rats.…”

Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

“…Previous reports show that JP2 is involved in the cardiogenesis of embryonic stem cells [27]. Knockdown of JP2 in HL-1 cells results in myocyte hypertrophy [21]. However, it seems that partial silencing of JP2 in cultured adult cardiomyocytes does not alter the morphology of cardiomyocytes [24].…”

A Mutation in TNNC1-encoded Cardiac Troponin C, TNNC1-A31S, Predisposes to Hypertrophic Cardiomyopathy and Ventricular Fibrillation

“…Although some HCM-associated mutations have been associated with sudden death susceptibility based on survival studies of the kindred hosting the mutations, there is a paucity of mechanistic insight into the arrhythmogenic state caused by these mutations (26). Early studies identifying "malignant mutations" in families, such as (␤-myosin heavy chain) MYH7-R403Q and (cardiac troponin T) TNNT2-R92W, were associated with decreased Kaplan-Meyer survival when compared with families hosting so-called "benign" HCM mutations; however, detailed …”