Zeidan Asad, Javadov Sabzali, Karmazyn Morris
Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
Cardiovasc Res. 2006 Oct 1;72(1):101-11. doi: 10.1016/j.cardiores.2006.06.024. Epub 2006 Jun 29.
Obesity is associated with increased leptin production, which may contribute to cardiac hypertrophy. Although leptin has been shown to produce cardiomyocyte hypertrophy, its mechanism of action is far from clear. Rho proteins have been suggested as major contributors to cardiac hypertrophy, although their potential role in mediating the effect of leptin has not been studied.
We determined the role of Rho and Rho-associated kinase (ROCK) as mediators of leptin-induced cell hypertrophy in cultured neonatal rat ventricular myocytes.
Leptin (3.1 nmol/L) significantly increased cell surface area by 32+/-5% and leucine incorporation by 43 +/- 7%. These effects were associated with significant activation of RhoA to 450 +/- 40% of pre-leptin levels that was attenuated by pretreatment with an anti-leptin receptor (anti-OBR) antibody (166 ng/mL) to 120 +/- 20% of control values. Both the RhoA inhibitor C3 exoenzyme and ROCK inhibitor Y-27632 potently attenuated leptin-induced increased cell surface area and leucine incorporation. The hypertrophic effect of leptin was associated with an increase in phosphorylation of the actin binding protein cofilin to 290 +/- 20% of control values. In addition, the increase in polymerization of actin, as reflected by a decrease in the G/F-actin ratio, was significantly inhibited by both the anti-OBR antibody and Y-27632. Leptin-induced hypertrophy was also attenuated by disruption of actin filaments with 50 nmol/L latrunculin B. RhoA pathway inhibitors and latrunculin B also both attenuated leptin-induced ERK1/2 and p38 activation.
Our results indicate that the activation of Rho and actin dynamics play a pivotal role in leptin signaling leading to the development of cardiomyocyte hypertrophy.
肥胖与瘦素分泌增加有关，这可能会导致心肌肥大。尽管已经证明瘦素可引起心肌细胞肥大，但其作用机制仍不清楚。Rho蛋白被认为是导致心肌肥大的主要因素，尽管尚未研究其在介导瘦素作用中的潜在作用。
我们确定了Rho和Rho相关激酶（ROCK）在培养的新生大鼠心室肌细胞中作为瘦素诱导的细胞肥大介质的作用。
瘦素（3.1 nmol/L）使细胞表面积显著增加32±5%，亮氨酸掺入量增加43±7%。这些作用与RhoA显著激活至瘦素处理前水平的450±40%相关，而用抗瘦素受体（抗OBR）抗体（166 ng/mL）预处理可将其减弱至对照值的120±20%。RhoA抑制剂C3外切酶和ROCK抑制剂Y-27632均有效减弱了瘦素诱导的细胞表面积增加和亮氨酸掺入。瘦素的肥大作用与肌动蛋白结合蛋白丝切蛋白的磷酸化增加至对照值的290±20%相关。此外，抗OBR抗体和Y-27632均显著抑制了肌动蛋白聚合增加，这通过G/F-肌动蛋白比率降低得以反映。用50 nmol/L拉特肌毒素B破坏肌动蛋白丝也减弱了瘦素诱导的肥大。RhoA途径抑制剂和拉特肌毒素B也均减弱了瘦素诱导的ERK1/2和p38激活。
我们的结果表明，Rho的激活和肌动蛋白动力学在瘦素信号传导导致心肌细胞肥大发展中起关键作用。
