Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension
Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension
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DOI：
10.1007/s00395-009-0017-3
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发表时间：
2009-09-01
影响因子：
9.5
通讯作者：
Leite-Moreira, Adelino F.
中科院分区：
文献类型：
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作者：
Correia-Pinto, Jorge;Henriques-Coelho, Tiago;Leite-Moreira, Adelino F.
尽管肺动脉高压（PH）选择性地使右心室（RV）超负荷，但左心室（LV）的神经内分泌激活和内在心肌功能障碍已被描述。为了确定PH下左室功能障碍发展的时间并阐明潜在的分子变化，在Wistar大鼠皮下注射60 mg/kg （MCT-4, n = 11; MCT-6, n = 11）或对照（Ctrl-4, n = 11; Ctrl-6, n = 11） 4周和6周后对其进行研究。从基线到等容（LVPiso）进行急性单次搏动收缩压逐步升高。这种血流动力学应力被用来检测左室表现的早期变化。通过测量血管紧张素转换酶（ACE）和内皮素-1 (ET-1) LV mRNA水平来评估神经体液活化。TUNEL法检测心肌细胞凋亡。通过腱蛋白c mRNA水平和间质胶原含量评估细胞外基质组成。用蛋白定量法研究左室肌球蛋白重链（Myosin heavy chain， MHC）组成。MCT治疗增加了左室压力和左室/左室重量比，但没有改变左室舒张末期压力或尺寸。基线左室功能障碍仅存在于MCT-6大鼠中。负荷后升高延长了MCT-4和MCT-6中tau和舒张末期压力尺寸的关系，甚至更多。两组均出现mhc -异构体开关、ACE上调和心肌细胞凋亡。严重PH大鼠发生与ET-1和tenascin-C过表达相关的左室功能障碍。然而，当只有左室分子改变，如MHC异构体开关、ACE上调和心肌凋亡时，舒张功能障碍可在血流动力学应激的早期阶段引起。
Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.