Popeye domain-containing 1 is down-regulated in failing human hearts

Abstract

Abstract. Congestive heart failure, a complex disease of heterogeneous etiology, involves alterations in the expression of multiple genes. The Popeye domain-containing (POPDC) family of three novel muscle-restricted genes (POPDC1-3) is evolutionarily conserved and developmentally regulated. In mice, POPDC1 has been shown to play an important role in skeletal and cardiac muscles subjected to injury or stress. However, it has never been explored in human hearts. In biopsies from non-failing and failing human hearts, we examined the cellular distribution of POPDC1 as well as the expression patterns of POPDC1-3 mRNAs. POPDC1 was visualized by immunohistochemistry and estimated by Western immunoblotting. The mRNA levels of POPDC1-3 and ß myosin heavy chain (MYHC7) were assessed using reverse transcription/quantitative polymerase chain reaction. POPDC1 was predominantly localized in the sarcolemma with an enhanced expression in the intercalated discs. In failing hearts, many cardiomyocytes appeared deformed and POPDC1 labeling was deranged. The three POPDC mRNAs were expressed in the four heart chambers with higher transcript levels in the ventricles compared to the atria. Heart failure concurred with reduced levels of POPDC1 mRNA and protein in the left ventricle. Correlation analyses of mRNA levels among the failing heart specimens indicated the coordinated regulation of POPDC1 with POPDC3 and of POPDC2 with MYHC7. It can be concluded that POPDC gene expression is modified in end-stage heart failure in humans in a manner suggesting regulatory and/or functional differences between the three family members and that POPDC1 is particularly susceptible to this condition.

Popeye Domain Containing 1 (Popdc1/Bves) Is a Caveolae-Associated Protein Involved in Ischemia Tolerance

“…This could be the outcome of the acute tissue injury but could also contribute to the concomitant reduction in LV performance. Previously, we reported the diminution of Popdc1 and its coding mRNA in end stage heart failure in humans that suggested a relationship between the evolution of myocardial dysfunction and the decrease in Popdc1 [19]. Interestingly, the expression level of LacZ (the product of the Popdc1LacZ allele) was not affected by I/R.…”

“…Whereas Popdc1 (Bves) has been extensively studied in normal and transformed epithelial cells of various origins [4]–[6], [8]–[12], [15], [17], [19], there have been fewer reports regarding the function of Popdc1 in muscles although these tissues are the predominant site of Popdc1 expression. In this work, we demonstrate that Popdc1 is a caveolae-associated protein essential for the maintenance of caveolae number and size and that Popdc1 deficiency impairs Ca 2+ handling, reduces the tolerance of I/R and oxidative stress, and abolishes ischemic and pharmacologic preconditioning.…”

“…Total RNA was isolated from frozen hearts as previously described [19], cDNA was prepared and qPCR was performed using SYBR Green for product detection. The primer sequences used were: Popdc1 , F: GCCTGCACCACTTTCTGC; R: CTCGATTGGCTTCATCTTGG.…”

“…We identified a marked reduction in Popdc1 expression in end stage failing human hearts [19]. In addition, Popdc1 -null mice did not develop any obvious heart defect but displayed impaired skeletal muscle regeneration [3] and maladaption of heart rhythmicity to adrenergic stress that might be related to the ability of Popdc1 and the other family members to bind cAMP and to interact with ion channels such as TREK-1 [20], [21].…”

Phosphoproteomic Profiling of Human Myocardial Tissues Distinguishes Ischemic from Non-Ischemic End Stage Heart Failure

“…POPD1 has been shown to play an important role in cardiac pacemaker cells, cellular adhesion, and cellular signaling, especially in times of stress [34], [35]. Some literature suggest that POPD1 content is decreased in human heart failure [36]. While the overall abundance of POPD1 was not changed between the three groups in our data, POPD1 phosphorylation at 2 sites was diminished in NIF heart relative to NF heart, while phosphorylation at these sites was minimally changed in IF (Table 4).…”