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Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.

Duan Q, Ni L, Wang P, Chen C, Yang L, Ma B, Gong W, Cai Z, Zou MH, Wang DW - Aging Cell (2016)

Bottom Line: Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure.Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo.These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.

No MeSH data available.


Related in: MedlinePlus

Cardiac XBP1 expression is increased in ISO infusion‐induced hypertrophic and failing heart. (A) Heart weight/body weight (HW/BW, grams) after ISO infusion. (B) Cross‐sectional area (CSA) of cardiomyocytes after ISO infusion. (C) Hemodynamic analysis of mice at 1 and 2 weeks of ISO infusion: (left) dP/dtmax (mmHg/s) and (right) dP/dtmin (mmHg/s). (D) Echocardiographic analysis of mice at 2 weeks of ISO infusion (LVPW, LV posterior wall thickness). (E) ANP mRNA expression in ISO‐treated mice. (F) Western blots of Grp78 and XBP1s in mouse hearts at 1 and 2 weeks of ISO infusion. (G) Western blot of Grp78 and XBP1s in mouse hearts after TAC treatment. Error bars indicate SEM. n = 6 for A–E. The blot is representative of at least four blots from four independent experiments; *P < 0.05 compared with control.
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acel12460-fig-0001: Cardiac XBP1 expression is increased in ISO infusion‐induced hypertrophic and failing heart. (A) Heart weight/body weight (HW/BW, grams) after ISO infusion. (B) Cross‐sectional area (CSA) of cardiomyocytes after ISO infusion. (C) Hemodynamic analysis of mice at 1 and 2 weeks of ISO infusion: (left) dP/dtmax (mmHg/s) and (right) dP/dtmin (mmHg/s). (D) Echocardiographic analysis of mice at 2 weeks of ISO infusion (LVPW, LV posterior wall thickness). (E) ANP mRNA expression in ISO‐treated mice. (F) Western blots of Grp78 and XBP1s in mouse hearts at 1 and 2 weeks of ISO infusion. (G) Western blot of Grp78 and XBP1s in mouse hearts after TAC treatment. Error bars indicate SEM. n = 6 for A–E. The blot is representative of at least four blots from four independent experiments; *P < 0.05 compared with control.

Mentions: The mice hypertrophy model was established using isoproterenol (ISO) infusion. We first characterized this model using morphological, hemodynamic, and echocardiographic analysis. As depicted in Fig. 1A–B, heart weight/body weight (HW/BW) and cross‐sectional area (CSA) of cardiomyocytes significantly increased after ISO infusion. Consistently, hemodynamic analysis confirmed a reduction of dP/dtmax (mmHg/s) and dP/dtmin (mmHg/s) as early as 1 week after ISO infusion (Fig. 1C). Further, echocardiographic analysis showed that LV posterior wall thickness (LVPW) was increased after ISO infusion (Fig. 1D). Consistently, myocardial atrial natriuretic peptide (ANP) mRNA, a marker associated with cardiac hypertrophy and heart failure, was also significantly increased in mouse hearts after ISO infusion (Fig. 1E). Taken together, these results indicate that cardiac hypertrophy gradually developed from 1 to 2 weeks after ISO infusion and cardiac function declined thereafter. Then, we further determined whether ISO infusion caused ER stress in hypertrophic hearts in vivo. As depicted in Fig. 1F, protein levels of the ER chaperone GRP78 and UPR transcription factor XBP1 were increased as early as 1 week and continue to rise at 2 weeks after ISO infusion (Fig. 1F), suggesting that ISO infusion caused aberrant ER stress in the early phase of cardiac hypertrophy.


Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.

Duan Q, Ni L, Wang P, Chen C, Yang L, Ma B, Gong W, Cai Z, Zou MH, Wang DW - Aging Cell (2016)

Cardiac XBP1 expression is increased in ISO infusion‐induced hypertrophic and failing heart. (A) Heart weight/body weight (HW/BW, grams) after ISO infusion. (B) Cross‐sectional area (CSA) of cardiomyocytes after ISO infusion. (C) Hemodynamic analysis of mice at 1 and 2 weeks of ISO infusion: (left) dP/dtmax (mmHg/s) and (right) dP/dtmin (mmHg/s). (D) Echocardiographic analysis of mice at 2 weeks of ISO infusion (LVPW, LV posterior wall thickness). (E) ANP mRNA expression in ISO‐treated mice. (F) Western blots of Grp78 and XBP1s in mouse hearts at 1 and 2 weeks of ISO infusion. (G) Western blot of Grp78 and XBP1s in mouse hearts after TAC treatment. Error bars indicate SEM. n = 6 for A–E. The blot is representative of at least four blots from four independent experiments; *P < 0.05 compared with control.
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acel12460-fig-0001: Cardiac XBP1 expression is increased in ISO infusion‐induced hypertrophic and failing heart. (A) Heart weight/body weight (HW/BW, grams) after ISO infusion. (B) Cross‐sectional area (CSA) of cardiomyocytes after ISO infusion. (C) Hemodynamic analysis of mice at 1 and 2 weeks of ISO infusion: (left) dP/dtmax (mmHg/s) and (right) dP/dtmin (mmHg/s). (D) Echocardiographic analysis of mice at 2 weeks of ISO infusion (LVPW, LV posterior wall thickness). (E) ANP mRNA expression in ISO‐treated mice. (F) Western blots of Grp78 and XBP1s in mouse hearts at 1 and 2 weeks of ISO infusion. (G) Western blot of Grp78 and XBP1s in mouse hearts after TAC treatment. Error bars indicate SEM. n = 6 for A–E. The blot is representative of at least four blots from four independent experiments; *P < 0.05 compared with control.
Mentions: The mice hypertrophy model was established using isoproterenol (ISO) infusion. We first characterized this model using morphological, hemodynamic, and echocardiographic analysis. As depicted in Fig. 1A–B, heart weight/body weight (HW/BW) and cross‐sectional area (CSA) of cardiomyocytes significantly increased after ISO infusion. Consistently, hemodynamic analysis confirmed a reduction of dP/dtmax (mmHg/s) and dP/dtmin (mmHg/s) as early as 1 week after ISO infusion (Fig. 1C). Further, echocardiographic analysis showed that LV posterior wall thickness (LVPW) was increased after ISO infusion (Fig. 1D). Consistently, myocardial atrial natriuretic peptide (ANP) mRNA, a marker associated with cardiac hypertrophy and heart failure, was also significantly increased in mouse hearts after ISO infusion (Fig. 1E). Taken together, these results indicate that cardiac hypertrophy gradually developed from 1 to 2 weeks after ISO infusion and cardiac function declined thereafter. Then, we further determined whether ISO infusion caused ER stress in hypertrophic hearts in vivo. As depicted in Fig. 1F, protein levels of the ER chaperone GRP78 and UPR transcription factor XBP1 were increased as early as 1 week and continue to rise at 2 weeks after ISO infusion (Fig. 1F), suggesting that ISO infusion caused aberrant ER stress in the early phase of cardiac hypertrophy.

Bottom Line: Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure.Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo.These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.

No MeSH data available.


Related in: MedlinePlus