Minhas Khalid M, Khan Shakil A, Raju Shubha V Y, Phan Alexander C, Gonzalez Daniel R, Skaf Mike W, Lee Kwangho, Tejani Ankit D, Saliaris Anastasios P, Barouch Lili A, O'Donnell Christopher P, Emala Charles W, Berkowitz Dan E, Hare Joshua M
The Johns Hopkins Medical Institutions, Cardiology Division, 720 Rutland Avenue, Ross 1059, Baltimore, MD 21205, USA.
J Physiol. 2005 Jun 1;565(Pt 2):463-74. doi: 10.1113/jphysiol.2005.084566. Epub 2005 Mar 10.
Impaired leptin signalling in obesity is increasingly implicated in cardiovascular pathophysiology. To explore mechanisms for leptin activity in the heart, we hypothesized that physiological leptin signalling participates in maintaining cardiac beta-adrenergic regulation of excitation-contraction coupling. We studied 10-week-old (before development of cardiac hypertrophy) leptin-deficient (ob/ob, n=12) and C57Bl/6 (wild-type (WT), n=15) mice at baseline and after recombinant leptin infusion (0.3 mg kg-1 day-1 for 28 days, n=6 in each group). Ob/ob-isolated myocytes had attenuated sarcomere shortening and calcium transients ([Ca2+]i) versus WT (P<0.01 for both) following stimulation of the beta-receptor (with isoproterenol (isoprenaline)) or at the post-receptor level (with forskolin and dibutryl-cAMP). In addition, sarcoplasmic reticulum (SR) Ca2+ stores were depressed. Leptin replenishment in ob/ob mice restored each of these abnormalities towards normal without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture. Immunoblots revealed alterations of several proteins involved in excitation-contraction coupling in the ob/ob mice, including decreased abundance of Gsalpha-52 kDa, as well as alterations in the expression of Ca2+ cycling proteins (increased SR Ca2+-ATPase, and depressed phosphorylated phospholamban). In addition, protein kinase A (PKA) activity in ob/ob mice was depressed at baseline and correctable towards the activity found in WT with leptin repletion, a finding that could account for impaired beta-adrenergic responsiveness. Taken together, these data reveal a novel link between the leptin signalling pathway and normal cardiac function and suggest a mechanism by which leptin deficiency or resistance may lead to cardiac depression.
肥胖状态下瘦素信号受损在心血管病理生理学中的作用日益受到关注。为了探究瘦素在心脏中的作用机制，我们推测生理状态下的瘦素信号参与维持心脏β-肾上腺素能对兴奋-收缩偶联的调节。我们研究了10周龄（心脏肥大形成前）的瘦素缺乏小鼠（ob/ob，n = 12）和C57Bl/6野生型小鼠（WT，n = 15），分别在基线状态以及重组瘦素输注后（0.3 mg kg-1 天-1，共28天，每组n = 6）进行观察。与野生型小鼠相比，ob/ob分离的心肌细胞在β-受体受刺激后（使用异丙肾上腺素）或在受体后水平（使用福斯可林和二丁酰环磷腺苷），肌节缩短和钙瞬变（[Ca2+]i）减弱（两者P均<0.01）。此外，肌浆网（SR）钙储备减少。给ob/ob小鼠补充瘦素可使上述各项异常恢复正常，且不影响心脏结构的大体指标（壁厚）或微观指标（细胞大小）。免疫印迹显示ob/ob小鼠中几种参与兴奋-收缩偶联的蛋白质发生改变，包括Gsα-52 kDa丰度降低，以及钙循环蛋白表达的改变（肌浆网钙ATP酶增加，磷酸化受磷蛋白降低）。此外，ob/ob小鼠的蛋白激酶A（PKA）活性在基线时降低，补充瘦素后可恢复至野生型小鼠的活性水平，这一发现可以解释β-肾上腺素能反应受损的原因。综上所述，这些数据揭示了瘦素信号通路与正常心脏功能之间的新联系，并提示了瘦素缺乏或抵抗可能导致心脏功能抑制的机制。
