The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM/ RCM). Mutations in many of the sarcomeric genes are causal for HCM/RCM. In most cases, these mutations result in increased Ca2+ sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM/ RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca2+ desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1–10 μM) decrease in contractility in a Ca2+-independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca2+ sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca2+-sensitive sarcomere function.
|Original language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|State||Published - Jul 2016|
Bibliographical notePublisher Copyright:
© 2016 the American Physiological Society.
- Calcium sensitivity
- Hypertrophic cardiomyopathy