Brody School of Medicine, Department of Physiology, East Carolina University, Greenville, North Carolina, United States of America.
PLoS One. 2013 Aug 30;8(8):e74116. doi: 10.1371/journal.pone.0074116. eCollection 2013.
Blood pressure increases with age, and dysfunction of the dopamine D3 receptor has been implicated in the pathogenesis of hypertension. To evaluate the role of the D3 receptor in aging-related hypertension, we assessed cardiac structure and function in differently aged (2 mo, 1 yr, 2 yr) wild type (WT) and young (2 mo) D3 receptor knockout mice (D3KO). In WT, systolic and diastolic blood pressures and rate-pressure product (RPP) significantly increased with age, while heart rate significantly decreased. Blood pressure values, heart rate and RPP of young D3KO were significantly elevated over age-matched WT, but similar to those of the 2 yr old WT. Echocardiography revealed that the functional measurements of ejection fraction and fractional shortening decreased significantly with age in WT and that they were significantly smaller in D3KO compared to young WT. Despite this functional change however, cardiac morphology remained similar between the age-matched WT and D3KO. Additional morphometric analyses confirmed an aging-related increase in left ventricle (LV) and myocyte cross-sectional areas in WT, but found no difference between age-matched young WT and D3KO. In contrast, interstitial fibrosis, which increased with age in WT, was significantly elevated in the D3KO over age-matched WT, and similar to 2 yr old WT. Western analyses of myocardial homogenates revealed significantly increased levels of pro- and mature collagen type I in young D3KO. Column zymography revealed that activities of myocardial MMP-2 and MMP-9 increased with age in WTs, but in D3KO, only MMP-9 activity was significantly increased over age-matched WTs. Our data provide evidence that the dopamine D3 receptor has a critical role in the emergence of aging-related cardiac fibrosis, remodeling, and dysfunction.
血压随年龄增长而升高，多巴胺 D3 受体功能障碍与高血压的发病机制有关。为了评估 D3 受体在与年龄相关的高血压中的作用，我们评估了不同年龄（2 个月、1 年、2 年）的野生型（WT）和年轻（2 个月）D3 受体敲除小鼠（D3KO）的心脏结构和功能。在 WT 中，收缩压和舒张压以及心率乘积（RPP）随年龄显著增加，而心率显著降低。年轻的 D3KO 的血压值、心率和 RPP 明显高于同龄 WT，但与 2 岁 WT 相似。超声心动图显示，WT 的射血分数和缩短分数的功能测量值随年龄显著降低，而 D3KO 与年轻 WT 相比明显更小。然而，尽管存在这种功能变化，但心脏形态在同龄 WT 和 D3KO 之间保持相似。额外的形态计量学分析证实，WT 中左心室（LV）和心肌细胞横截面积随年龄增长而增加，但在同龄 WT 和 D3KO 之间没有差异。相比之下，WT 中随年龄增加的间质纤维化在 D3KO 中明显升高，与 2 岁 WT 相似。心肌匀浆的 Western 分析显示，年轻的 D3KO 中前胶原和成熟型胶原 I 的水平显著增加。柱层凝胶电泳显示，WT 中 MMP-2 和 MMP-9 的心肌活性随年龄增加而增加，但在 D3KO 中，只有 MMP-9 的活性明显高于同龄 WT。我们的数据提供了证据，表明多巴胺 D3 受体在与年龄相关的心脏纤维化、重塑和功能障碍的出现中具有关键作用。
