Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Abstract

Young ME, Marchase RB, Chatham JC. Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function. Am J Physiol Heart Circ Physiol 306: H1231-H1239, 2014. First published February 28, 2014 doi:10.1152/ajpheart.00075.2014.-The endoplasmic reticulum (ER) Ca 2ϩ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca 2ϩ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ( cr STIM1-KO) mouse. In cardiomyocytes isolated from cr STIM1-KO mice, STIM1 expression was reduced by ϳ92% with no change in the expression of related store-operated Ca 2ϩ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that cr STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in cr S-TIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in cr STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in cr STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function. store-operated Ca 2ϩ entry; STIM1; cardiomyocytes; ER stress; mitochondria

STIM1 enhances SR Ca 2+ content through binding phospholamban in rat ventricular myocytes

“…These animals develop a progressive dilated cardiomyopathy starting around 20 wk of age and die prematurely starting around week 40 (46). Although in young STIM1 cardiacspecific knockout mice there is no significant dysfunction, ER/ SR stress increases in these animals starting around 12 wk (46). It is thus plausible that this ER/SR stress might arise from the decreases in SR Ca 2+ content (a common marker of ER/SR stress) (47) due to the mechanisms presented here.…”

“…The additional investigations here indicate that this regulation arises from a novel mechanism: STIM1 binds to un-p-PLN and, by this means, STIM1 increases SERCA2a-mediated Ca 2+ uptake into the SR. With the lower expression of STIM1 as seen under physiological conditions, these data suggest that STIM1 moderates SERCA2a-dependent [Ca 2+ ] SR . This function is probably important, as the long-term absence of STIM1 in cardiac-specific STIM1 knockout animals underlies serious disease (46). These animals develop a progressive dilated cardiomyopathy starting around 20 wk of age and die prematurely starting around week 40 (46).…”

“…This function is probably important, as the long-term absence of STIM1 in cardiac-specific STIM1 knockout animals underlies serious disease (46). These animals develop a progressive dilated cardiomyopathy starting around 20 wk of age and die prematurely starting around week 40 (46). Although in young STIM1 cardiacspecific knockout mice there is no significant dysfunction, ER/ SR stress increases in these animals starting around 12 wk (46).…”

Mitochondrial dysfunction in cardiac aging

“…CHOP, Lon, and Trx2 are key proteins in the stress response pathways. CHOP is activated by the marking of unfolded proteins by BiP/GRP78, helping to prevent aggregation of the misfolded proteins [199]. Lon and Trx2 have recently been shown to play a key role in decreasing ROS in the mitochondria and preventing apoptosis within the cardiomyocytes.…”

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

“…A significant body of evidence suggests that the ER’s role in cellular stress and cell death is related to Ca 2+ and intricate control of autophagy and apoptosis cascades [246–248]. In addition, Ca 2+ -mediated ER chaperones, such as calreticulin, are involved in protein folding, such that dysregulation of Ca 2+ leads to alterations in chaperone capacity, triggering cellular stress [249,250]. …”