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Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

ABSTRACT: Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R-like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2?, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice. Under unstressed conditions, cardiac PERK knockout had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK knockout mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis, and exacerbated lung remodeling in comparison with wild-type mice. PERK knockout also dramatically attenuated cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced congestive heart failure.

SUBMITTER: Liu X

PROVIDER: S-EPMC4162806 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

Liu Xiaoyu X Kwak Dongmin D Lu Zhongbing Z Xu Xin X Fassett John J Wang Huan H Wei Yidong Y Cavener Douglas R DR Hu Xinli X Hall Jennifer J Bache Robert J RJ Chen Yingjie Y

Hypertension (Dallas, Tex. : 1979) 20140623 4

Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R-like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2α, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of P ...[more]

PMID: 24958502

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Project description:Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although 18F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with 18F-FDG can be serially imaged in the early stages of pressure-overload-induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. 18F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 μL vs. 23.8 ± 1.7 μL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = -0.669, P = 0.010). PET imaging identified significantly higher left ventricular 18F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The 18F-FDG signal correlated with ejection fraction (r = -0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using 18F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

Project description:Background SENP1 (sentrin/small ubiquitin-like modifier-specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload-induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac-specific SENP1 knockdown markedly exacerbated transverse aortic constriction-induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus-mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1-JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte-specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy-promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post-transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload-induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

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Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

Publications

Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

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