Koch Sheryl E, Mann Adrien, Jones Shannon, Robbins Nathan, Alkhattabi Abdullah, Worley Mariah C, Gao Xu, Lasko-Roiniotis Valerie M, Karani Rajiv, Fulford Logan, Jiang Min, Nieman Michelle, Lorenz John N, Rubinstein Jack
aDepartment of Internal Medicine, Division of Cardiovascular Health and Disease bDepartment of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA.
J Hypertens. 2017 Mar;35(3):602-611. doi: 10.1097/HJH.0000000000001213.
Hypertension (increased afterload) results in cardiomyocyte hypertrophy leading to left ventricular hypertrophy and subsequently, heart failure with preserved ejection fraction. This study was performed to test the hypothesis that transient receptor potential vanilloid 2 subtype (TRPV2) function regulates hypertrophy under increased afterload conditions.
We used functional (pore specific) TRPV2 knockout mice to evaluate the effects of increased afterload-induced stretch on cardiac size and function via transverse aortic constriction (TAC) as well as hypertrophic stimuli including adrenergic and angiotensin stimulation via subcutaneous pumps. Wild-type animals served as control for all experiments. Expression and localization of TRPV2 was investigated in wild-type cardiac samples. Changes in cardiac function were measured in vivo via echocardiography and invasive catheterization. Molecular changes, including protein and real-time PCR markers of hypertrophy, were measured in addition to myocyte size.
TRPV2 is significantly upregulated in wild-type mice after TAC, though not in response to beta-adrenergic or angiotensin stimulation. TAC-induced stretch stimulus caused an upregulation of TRPV2 in the sarcolemmal membrane. The absence of functional TRPV2 resulted in significantly reduced left ventricular hypertrophy after TAC, though not in response to beta-adrenergic or angiotensin stimulation. The decreased development of hypertrophy was not associated with significant deterioration of cardiac function.
We conclude that TRPV2 function, as a stretch-activated channel, regulates the development of cardiomyocyte hypertrophy in response to increased afterload.
高血压（后负荷增加）会导致心肌细胞肥大，进而引起左心室肥大，随后出现射血分数保留的心力衰竭。本研究旨在验证以下假设：瞬时受体电位香草酸亚型2（TRPV2）的功能在增加后负荷的情况下调节肥大。
我们使用功能性（孔特异性）TRPV2基因敲除小鼠，通过横向主动脉缩窄（TAC）评估增加后负荷诱导的牵张对心脏大小和功能的影响，以及通过皮下泵进行肾上腺素能和血管紧张素刺激等肥大刺激。野生型动物作为所有实验的对照。在野生型心脏样本中研究TRPV2的表达和定位。通过超声心动图和侵入性导管插入术在体内测量心脏功能的变化。除了测量心肌细胞大小外，还测量了包括肥大的蛋白质和实时PCR标志物在内的分子变化。
TAC后野生型小鼠中TRPV2显著上调，但对β-肾上腺素能或血管紧张素刺激无反应。TAC诱导的牵张刺激导致肌膜中TRPV2上调。功能性TRPV2的缺失导致TAC后左心室肥大显著减轻，但对β-肾上腺素能或血管紧张素刺激无反应。肥大发展的减少与心脏功能的显著恶化无关。
我们得出结论，TRPV2作为一种牵张激活通道，其功能可调节心肌细胞肥大对增加后负荷的反应。
