Myocardial hypertrophy is a response to environmental stress that allows augmentation of pump function and reduces wall stress. Importantly, the transition from hypertrophy to heart failure is associated with a decrease in cardiac contractility, ventricular remodeling and fibrosis, and myocyte loss.
One of the most highly characterized hypertrophic signaling cascades involves the calcium dependent serine/threonine protein phosphatase calcineurin. Elevated intracellular calcium levels activate calcineurin, which in turn then dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT) in the cytoplasm. This leads to its translocation to the nucleus and the subsequent activation of hypertrophy-associated genes.
In this paper the authors identify a novel GTPase, cdc42, that was specifically activated in the heart after pressure overload. Mice with a heart-specific deletion of cdc42 developed greater levels of hypertrophy than wild-type controls under neuroendocrine stress, and also transitioned more quickly into heart failure. Furthermore, knockout mice showed enhanced exercise-induced hypertrophy and an increased susceptibility to sudden death. The lack of cdc42 led to an increase in NFAT activity, suggesting that cdc42 is needed to reduce hypertrophy and prevent the transition to heart failure.
Cdc42 is a novel signaling pathway that may reduce hypertrophy and heart failure when activated. As such it could be a target for novel pharmaceutical therapies designed to decrease myocardial hypertrophy and heart failure in humans.
• Maillet M, Lynch JM, Sanna B et al. Cdc42 is an antihypertrophic molecular switch in the mouse heart. J. Clin. Invest. 2009;119(10):3079-3088
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax
Dr Alistair C. Lindsay, Dr Katie Qureshi, Dr Jon Spiro, Dr Hussain Contractor
Figure 1 – http://heart.bmj.com/site/misc/Feb1.pdf