Cardiomyocyte-specific disruption of Serca2 in adult mice causes sarco(endo)plasmic reticulum stress and apoptosis.
Reduced sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA2) contributes to the impaired cardiomyocyte Ca(2+) homeostasis observed in heart failure. We hypothesized that a reduction in SERCA2 also elicits myocardial ER/SR stress responses, including unfolded protein responses (UPR) and cardiomyocyte apoptosis, which may additionally contribute to the pathophysiology of this condition. Left ventricular myocardium from mice with cardiomyocyte-specific tamoxifen-inducible disruption of Serca2 (SERCA2 KO) was compared with aged-matched controls. In SERCA2 KO hearts, SERCA2 protein levels were markedly reduced to 2% of control values at 7 weeks following tamoxifen treatment. Serca2 disruption caused increased abundance of the ER stress-associated proteins CRT, GRP78, PERK, and eIF2α and increased phosphorylation of PERK and eIF2α, indicating UPR induction. Pro-apoptotic signaling was also activated in SERCA2 KO, as the abundance of CHOP, caspase 12, and Bax was increased. Indeed, TUNEL staining revealed an increased fraction of cardiomyocytes undergoing apoptosis in SERCA2 KO. ER-Tracker staining additionally revealed altered ER structure. These findings indicate that reduction in SERCA2 protein abundance is associated with marked ER/SR stress in cardiomyocytes, which induces UPR, apoptosis, and ER/SR structural alterations. This suggests that reduced SERCA2 abundance or function may contribute to the phenotype of heart failure also through induction of ER/SR stress responses.
Department of Pathophysiology, PLA General Hospital, Beijing 100853, China. xiuhauliu98@yahoo.com.cn
Xiu Hua
XH
Liu
Zhen Ying
ZY
Zhang
Kristin Brevik
KB
Andersson
Cathrine
C
Husberg
Ulla H
UH
Enger
Morten G
MG
Ræder
Geir
G
Christensen
William E
WE
Louch
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013629:Tamoxifen / Q000633:toxicity; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D002118:Calcium; D037282:Calreticulin; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013629:Tamoxifen; D051742:Transcription Factor CHOP; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C000717248:Hspa5 protein, mouse; C531557:eIF2alpha kinase, mouse; C506947:Atp2a2 protein, mouse