Frequency-dependent contractile strength in mice over- and underexpressing the sarco(endo)plasmic reticulum calcium-ATPase
Frequency-dependent contractile strength in mice over- and underexpressing the sarco(endo)plasmic reticulum calcium-ATPase
复制标题
DOI：
10.1152/ajpregu.00508.2006
复制
发表时间：
2007-07-01
影响因子：
2.8
通讯作者：
Janssen, Paul M. L.
中科院分区：
文献类型：
--
作者：
Hiranandani, Nitisha;Raman, Sripriya;Janssen, Paul M. L.
在分子水平上，终末期心力衰竭的显著标志之一是肌浆网ATPase蛋白[SERCA，SERCA]功能和/或表达的降低。通常认为，SERCA泵活性降低是导致心功能下降的主要原因。为了建立功能关系，我们评估了在没有其他显著分子变化的情况下，SERCA活性水平的变化如何影响健康心肌的基本收缩功能。我们研究了从高表达SERCA(转基因，TG)、低表达SERCA2a(杂合敲除，Het)的小鼠心脏及其各自的野生型(WT)小鼠心脏分离的超薄小梁的基线收缩功能、频率依赖的激活和P-肾上腺素能反应。在生理温度和频率下，SERCA1a小鼠在4~8赫兹的频率下与WT小鼠相比，发育力增加(与4赫兹时增加90%相似)，在10~14赫兹时的发育力与WT鼠相当。在1 mU M异丙肾上腺素存在下，TG和WT小鼠在4赫兹时的力量发展是相似的。在Het小鼠中，发育的力在频率范围的低端(4-8赫兹)几乎相同，但在更高的频率下略有降低(14赫兹时P<；0.05)。在1MU M异丙肾上腺素存在下，4赫兹产生的力与WT小鼠相同。与正常水平相比，SERCA活性的增加只在亚生理频率促进了力量的发育。SERCA活性的降低仅表现为在较高频率范围内作用力的抑制。因此，关于SERCA活性和收缩能力之间的相关性的概括可能非常含糊，因为这种关系严重依赖于其他因素，包括刺激频率。
One of the prominent markers of end-stage heart failure at the molecular level is a decrease in function and/or expression of the sarcoplasmic reticulum ATPase protein [sarco(endo)plasmic reticulum calcium-ATPase, SERCA]. It has been often postulated that a decrease in SERCA pump activity can contribute in a major way to decreased cardiac function. To establish a functional relationship, we assessed how alterations in SERCA activity level affect basic contractile function in healthy myocardium devoid of other significant molecular changes. We investigated baseline contractile function, frequency-dependent activation, and P-adrenergic response in ultrathin trabeculae isolated from hearts of mice overexpressing SERCA (transgenic, TG), underexpressing SERCA2a (heterozygous knockout, Het), and their respective wild-type (WT) littermates. At physiological temperature and frequency, compared with their respective WT littermates, SERCA 1 a mice displayed increased developed force at frequencies of 4-8 Hz (similar to 90% increase at 4 Hz) and force equal to WT mice at 10-14 Hz. Force development at 4 Hz in presence of 1 mu M isoproterenol was similar in TG and WT mice. In Het mice, developed force was nearly identical at the lower end of the frequency range (4-8 Hz) but slightly depressed at higher frequency (P < 0.05 at 14 Hz). In presence of 1 mu M isoproterenol, developed force at 4 Hz was equal to that in WT mice. Compared with normal levels, increased SERCA activity enhanced force development only at subphysiological frequencies. A reduction in SERCA activity only showed a depression of force at the higher frequency range. Thus generalizations regarding the correlation between SERCA activity and contractility can be highly ambiguous, because this relationship is critically dependent on other factors including stimulation frequency.