Jara Zaira Palomino, Icimoto Marcelo Yudi, Yokota Rodrigo, Ribeiro Amanda Aparecida, Dos Santos Fernando, de Souza Leandro Ezequiel, Watanabe Ingrid Kazue Mizuno, Franco Maria do Carmo, Pesquero Jorge Luiz, Irigoyen Maria Claudia, Casarini Dulce Elena
Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Cleveland Clinic, Cleveland, OH, United States.
Front Med (Lausanne). 2019 Jan 23;5:365. doi: 10.3389/fmed.2018.00365. eCollection 2018.
Tonin, a serine-protease that forms Angiotensin II (AngII) from angiotensinogen, is increased in failing human heart samples. Increased blood pressure (BP) and decreased heart rate (HR) variabilities are associated with higher risk of cardiovascular morbidity. Losartan has been used to reduce hypertension and, therefore, lowers the risk of fatal and non-fatal cardiovascular events. Determination of tonin's impact on BP and HR variabilities as well as the impact of losartan remain questions to be elucidated. Evaluation of cardiovascular autonomic profile in transgenic mice overexpressing the rat tonin enzyme TGM'(rton) and the impact of AT1 receptor blocker, losartan. Male C57BL/6 (WT) and TGM'(rTon) mice were cannulated for recording BP (Windaq, 4 MHz) for 30 min at baseline and 30 min after losartan injection (20 mg/kg). BP and HR variabilities were analyzed in time and frequency domain method. Low-frequency (LF) and high-frequency (HF) components were identified for sympathetic and parasympathetic modulations analysis. Ang I, AngII, and Ang1-7 were quantified by high performance liquid chromatography method. The total enzymatic activity for AngI, AngII, and Ang1-7 formation was evaluated in the heart and plasma by Liquid chromatography mass spectrometry (LC-MS/MS). At the baseline TGM'(rTon) exhibited higher BP, lower cardiac LF, higher cardiac HF, lower LF/HF, and lower alpha index than wild type (WT). After losartan injection, TGM'(rTon) mice presented an additional decrease in cardiac LF and increase in HF in relation to baseline and WT. In the vasculature, losartan caused decreased in BP and LF of systolic BP in WT mice in relation to its baseline. A similar effect was observed in the BP of TGM'(rTon) mice; however, LF of systolic BP increased compared to baseline. Our data also indicates that AT1R receptor signaling has been altered in TGM'(rTon)mice. Interestingly, the dynamics of the renin-angiotensin system kinetics change, favoring production of Ang1-7. Autonomic evaluation of TGM'(rTon) mice indicates an unclear prognosis for diseases that affect the heart. HR variability in TGM'(rTon) mice indicates high risk of morbidity, and sympathetic and parasympathetic modulation indicate low risk of morbidity. The low risk of morbidity could be the biased production of Ang1-7 in the heart and circulation; however, the altered response of AT1R in the TGM'(rTon) remains to be elucidated, as well aswhether that signaling is pro-protection or pro-pathology.
托宁是一种能将血管紧张素原转化为血管紧张素II（AngII）的丝氨酸蛋白酶，在衰竭的人类心脏样本中含量增加。血压（BP）升高和心率（HR）变异性降低与心血管疾病发病率较高相关。氯沙坦已被用于降低高血压，从而降低致命和非致命心血管事件的风险。托宁对BP和HR变异性的影响以及氯沙坦的影响仍有待阐明。评估过表达大鼠托宁酶TGM'（rton）的转基因小鼠的心血管自主神经特征以及AT1受体阻滞剂氯沙坦的影响。雄性C57BL/6（野生型）和TGM'（rTon）小鼠插管记录基线时30分钟和注射氯沙坦（20mg/kg）后30分钟的BP（Windaq，4MHz）。采用时域和频域方法分析BP和HR变异性。识别低频（LF）和高频（HF）成分用于交感神经和副交感神经调制分析。通过高效液相色谱法对血管紧张素I、AngII和Ang1-7进行定量。通过液相色谱质谱联用（LC-MS/MS）评估心脏和血浆中血管紧张素I、AngII和Ang1-7形成的总酶活性。在基线时，TGM'（rTon）小鼠的BP较高，心脏LF较低，心脏HF较高，LF/HF较低，α指数低于野生型（WT）。注射氯沙坦后，TGM'（rTon）小鼠的心脏LF相对于基线和WT进一步降低，HF增加。在血管系统中，氯沙坦使野生型小鼠的BP和收缩压LF相对于其基线降低。在TGM'（rTon）小鼠的BP中观察到类似的效果；然而，收缩压LF相对于基线增加。我们的数据还表明，TGM'（rTon）小鼠的AT1R受体信号发生了改变。有趣的是，肾素-血管紧张素系统动力学发生了变化，有利于Ang1-7的产生。对TGM'（rTon）小鼠的自主神经评估表明，影响心脏的疾病预后不明确。TGM'（rTon）小鼠的HR变异性表明发病风险高，交感神经和副交感神经调制表明发病风险低。发病风险低可能是由于心脏和循环中Ang1-7的偏向性产生；然而，TGM'（rTon）中AT1R的改变反应以及该信号是促保护还是促病理仍有待阐明。
