Ataxia‐Telangiectasia Mutated Kinase: A Potential New Target for Suppressing Inflammation in Heart Failure?

A taxia-telangiectasia mutated (ATM) kinase, the mutation of which causes the autosomal recessive disease ataxiatelangiectasia, plays an essential role in the maintenance of genome stability (reviewed in ref. 1). ATM (a serine/threonine protein kinase) senses DNA double-strand breaks and phosphorylates several key proteins to initiate the DNA damage response, leading to cell cycle arrest, DNA repair, or apoptosis. In fact, ATM is one of the master regulators of the cellular response to radiation-induced DNA damage and a key determinant of radiosensitivity. DNA damage leads to activation of ATM kinase activity and phosphorylation of a number of downstream targets such as p53, CHK2, and KAP1. This activation triggers cell cycle checkpoints, arrest, and delays in the G1, S, and G2 phases of the cell cycle and enables DNA repair of double-stranded breaks both by homologous recombination and by non-homologous end joining. Hence, fibroblasts and tumor cells are radiosensitized to x-ray radiation therapy in culture by pharmacological ATM inhibition, or by ATM mutation and deletion. ATM deficiency has been shown to sensitize cells to inhibition of poly (ADPribose) polymerase (PARP), an enzyme involved in DNA repair and apoptosis. Conversely, abnormally active ATM also impairs DNA repair by homologous recombination and thereby sensitizes cells to PARP inhibition. Thus, timely activation and inactivation of ATM are both necessary for efficient repair, and any ATM perturbation could inhibit the ability of cells to resist DNA damage. Clinically, it has been shown that cells isolated from patients with ataxia telangiectasia lacking functional ATM are sensitive to ionizing radiation. The chemotherapy drug doxorubicin also activates ATM through the production of superoxide radicals and induces apoptosis via p53. However, the role of ATM in myocardial infarction (MI) has not been studied as extensively as cancer although ATM-dependent signaling has been suggested to play a role in the development of atherosclerotic vascular disease. Heart failure usually leads to increased chamber diameter which results in increased loading capacity of the heart represented by increased left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV). Increased LVESV is suggested as one of the major determinants of survival, post-MI. Low-level but progressive loss of myocytes in the chronically overloaded heart is believed to contribute to cardiac remodeling and contractile failure (reviewed in ref. 11). Apoptosis in the heart following MI can be triggered by activation of G-protein coupled receptors (GPCRs), cytokines, and increased generation of ROS. Several kinases including ASK1 (apoptosis signal-regulating kinase 1), p38MAPK, JNK (c-Jun N-terminal kinase), CaMKII as well as protein kinase C-dependent transcriptional upregulation of the pro-apoptotic protein NIX (also known as BNIP3L) target mitochondria. CaMKII is potentially the convergence of proapoptotic signaling because it is activated by both Ca and regulated production of NADPH oxidase (NOX)-derived ROS, downstream of angiotensin II-induced stimulation of GPCRs. Apoptotic cell death is counteracted by pro-survival pathways, such as activation of Akt and proto-oncogene serine-threonine protein kinase (PIM1) and inactivation of glycogen synthase kinase 3ß (GSK3b). Programmed necrosis is a different type of cell death that has also been suggested to be important in heart disease. Necrosis is accompanied by early loss of plasma membrane and organelle integrity and striking inflammation. Inflammation can contribute to extracellular matrix remodeling and development of contractile failure. An important feature of the programmed necrosis is opening of the mitochondrial permeability transition pore (MPTP) in response to mitochondrial Ca and perhaps oxidative stress. Opening of MPTP causes collapse of mitochondrial membrane potential and ATP production and triggers necrosis. It has also been shown there is crosstalk between the apoptotic and necrotic The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University Medical Center, Richmond, VA. Correspondence to: Rakesh C. Kukreja, PhD, Scientific Director, Pauley Heart Center, Virginia Commonwealth University, 1101 East Marshall Street, Sanger Hall, Rm 7020d, Richmond, VA 23298-0204. E-mail: [email protected] J Am Heart Assoc. 2014;3:e001591 doi: 10.1161/JAHA.114.001591. a 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.