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Abstract：
UNASSIGNED: In hypertension (HTN), biomechanical stress may drive matrix remodeling through dysfunctional VSMC activity. Prior evidence has indicated VSMC tension-induced signaling through the serum and glucocorticoid inducible kinase-1 (SGK-1) can impact cytokine abundance. Here, we hypothesize that SGK-1 impacts production of additional aortic pathologic markers (APMs) representing VSMC dysfunction in HTN.
UNASSIGNED: Aortic VSMC expression of APMs was quantified by QPCR in cyclic biaxial stretch (Stretch) +/- AngiotensinII (AngII). APMs were selected to represent VSMC dedifferentiated transcriptional activity, specifically Interleukin-6 (IL-6), Cathepsin S (CtsS), Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). To further assess the effect of tension alone, abdominal aortic rings from C57Bl/6 WT mice were held in a myograph at experimentally derived optimal tension (OT) or OT + 30% +/-AngII. Dependence on SGK-1 was assessed by treating with EMD638683 (SGK-1 inhibitor) and APMs were measured by QPCR. Then, WT and smooth muscle cell specific SGK-1 heterozygous knockout (SMC-SGK-1KO+/-) mice had AngII-induced HTN. Systolic blood pressure and mechanical stress parameters were assessed on Day 0 and Day 21. Plasma was analyzed by ELISA to quantify APMs. Statistical analysis was performed by ANOVA.
UNASSIGNED: In cultured aortic VSMCs, expression of all APMs was increased in response to biomechanical stimuli (Stretch +/-AngII,). Integrating the matrix contribution to signal transduction in the aortic rings led to IL-6 and CysC demonstrating SGK-1 dependence in response to elevated tension and interactive effect with concurrent AngII stimulation. CtsS and TNC, on the other hand, primarily responded to AngII, and OPG expression was unaffected in aortic ring experimentation. Both mouse strains had >30% increase in blood pressure with AngII infusion, reduced aortic distensibility and increased PPV, indicating increased aortic stiffness. In WT + AngII mice, IL-6, CtsS, CysC, and TNC plasma levels were significantly elevated, but these APMs were unaffected by HTN in the SMC-SGK-1KO+/- +AngII mice, suggesting SGK-1 plays a major role in VSMC biomechanical signaling to promote dysfunctional production of selected APMs.
UNASSIGNED: In HTN, changes in the plasma levels of markers associated with aortic matrix homeostasis can reflect remodeling driven by mechanobiologic signaling in dysfunctional VSMCs, potentially through the activity of SGK-1. Further defining these pathways may identify therapeutic targets to reduce cardiovascular morbidity and mortality.
UNASSIGNED: Aortic VSMC expression of APMs was quantified by QPCR in cyclic biaxial stretch (Stretch) +/- AngiotensinII (AngII). APMs were selected to represent VSMC dedifferentiated transcriptional activity, specifically Interleukin-6 (IL-6), Cathepsin S (CtsS), Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). To further assess the effect of tension alone, abdominal aortic rings from C57Bl/6 WT mice were held in a myograph at experimentally derived optimal tension (OT) or OT + 30% +/-AngII. Dependence on SGK-1 was assessed by treating with EMD638683 (SGK-1 inhibitor) and APMs were measured by QPCR. Then, WT and smooth muscle cell specific SGK-1 heterozygous knockout (SMC-SGK-1KO+/-) mice had AngII-induced HTN. Systolic blood pressure and mechanical stress parameters were assessed on Day 0 and Day 21. Plasma was analyzed by ELISA to quantify APMs. Statistical analysis was performed by ANOVA.
UNASSIGNED: In cultured aortic VSMCs, expression of all APMs was increased in response to biomechanical stimuli (Stretch +/-AngII,). Integrating the matrix contribution to signal transduction in the aortic rings led to IL-6 and CysC demonstrating SGK-1 dependence in response to elevated tension and interactive effect with concurrent AngII stimulation. CtsS and TNC, on the other hand, primarily responded to AngII, and OPG expression was unaffected in aortic ring experimentation. Both mouse strains had >30% increase in blood pressure with AngII infusion, reduced aortic distensibility and increased PPV, indicating increased aortic stiffness. In WT + AngII mice, IL-6, CtsS, CysC, and TNC plasma levels were significantly elevated, but these APMs were unaffected by HTN in the SMC-SGK-1KO+/- +AngII mice, suggesting SGK-1 plays a major role in VSMC biomechanical signaling to promote dysfunctional production of selected APMs.
UNASSIGNED: In HTN, changes in the plasma levels of markers associated with aortic matrix homeostasis can reflect remodeling driven by mechanobiologic signaling in dysfunctional VSMCs, potentially through the activity of SGK-1. Further defining these pathways may identify therapeutic targets to reduce cardiovascular morbidity and mortality.
摘要：
■在高血压（HTN）中，生物力学应力可能通过功能失调的VSMC活动驱动基质重塑。先前的证据表明,通过血清和糖皮质激素诱导的激酶-1(SGK-1)的VSMC张力诱导的信号传导可以影响细胞因子丰度。这里,我们假设SGK-1会影响代表HTN中VSMC功能障碍的其他主动脉病理标志物(APM)的产生.
■通过QPCR在循环双轴拉伸(拉伸)+/-血管紧张素II(AngII)中定量APM的主动脉VSMC表达。选择APM代表VSMC去分化转录活性，特别是白细胞介素-6（IL-6），组织蛋白酶S(CtsS),胱抑素C(CysC),骨保护素(OPG),和TenascinC（TNC）。为了进一步评估单独的张力的影响，将来自C57Bl/6WT小鼠的腹主动脉环以实验得出的最佳张力（OT）或OT30％/-AngII保持在肌电图中。通过用EMD638683(SGK-1抑制剂)处理来评估对SGK-1的依赖性,并且通过QPCR测量APM。然后，WT和平滑肌细胞特异性SGK-1杂合子敲除(SMC-SGK-1KO+/-)小鼠具有AngII诱导的HTN。在第0天和第21天评估收缩压和机械应力参数。通过ELISA分析血浆以定量APM。通过ANOVA进行统计分析。
■在培养的主动脉VSMC中，响应于生物力学刺激，所有APM的表达均增加(拉伸+/-AngII，).整合基质对主动脉环中信号转导的贡献导致IL-6和CysC表现出SGK-1依赖性，以响应于升高的张力和同时的AngII刺激的相互作用作用。CTSS和TNC，另一方面,主要是对AngII的回应，在主动脉环实验中OPG表达不受影响。两种小鼠品系均有>30%的血压增加与AngII输注，降低主动脉扩张性和增加PPV，表明主动脉僵硬度增加。在WT+AngII小鼠中，IL-6,CtsS,CysC,和TNC血浆水平显著升高，但是在SMC-SGK-1KO+/-+AngII小鼠中，这些APM不受HTN的影响，表明SGK-1在VSMC生物力学信号传导中起主要作用，以促进选定APM的功能失调。
■在HTN中，与主动脉基质稳态相关的血浆标志物水平的变化可以反映功能失调的VSMC中机械生物学信号驱动的重塑，可能通过SGK-1的活动。进一步定义这些途径可以确定降低心血管发病率和死亡率的治疗靶标。
■通过QPCR在循环双轴拉伸(拉伸)+/-血管紧张素II(AngII)中定量APM的主动脉VSMC表达。选择APM代表VSMC去分化转录活性，特别是白细胞介素-6（IL-6），组织蛋白酶S(CtsS),胱抑素C(CysC),骨保护素(OPG),和TenascinC（TNC）。为了进一步评估单独的张力的影响，将来自C57Bl/6WT小鼠的腹主动脉环以实验得出的最佳张力（OT）或OT30％/-AngII保持在肌电图中。通过用EMD638683(SGK-1抑制剂)处理来评估对SGK-1的依赖性,并且通过QPCR测量APM。然后，WT和平滑肌细胞特异性SGK-1杂合子敲除(SMC-SGK-1KO+/-)小鼠具有AngII诱导的HTN。在第0天和第21天评估收缩压和机械应力参数。通过ELISA分析血浆以定量APM。通过ANOVA进行统计分析。
■在培养的主动脉VSMC中，响应于生物力学刺激，所有APM的表达均增加(拉伸+/-AngII，).整合基质对主动脉环中信号转导的贡献导致IL-6和CysC表现出SGK-1依赖性，以响应于升高的张力和同时的AngII刺激的相互作用作用。CTSS和TNC，另一方面,主要是对AngII的回应，在主动脉环实验中OPG表达不受影响。两种小鼠品系均有>30%的血压增加与AngII输注，降低主动脉扩张性和增加PPV，表明主动脉僵硬度增加。在WT+AngII小鼠中，IL-6,CtsS,CysC,和TNC血浆水平显著升高，但是在SMC-SGK-1KO+/-+AngII小鼠中，这些APM不受HTN的影响，表明SGK-1在VSMC生物力学信号传导中起主要作用，以促进选定APM的功能失调。
■在HTN中，与主动脉基质稳态相关的血浆标志物水平的变化可以反映功能失调的VSMC中机械生物学信号驱动的重塑，可能通过SGK-1的活动。进一步定义这些途径可以确定降低心血管发病率和死亡率的治疗靶标。
