Cardiomyocyte apoptosis

Sato M, Bagchi D, Tosaki A and Das DK. 2001. Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. Free Radic Biol Med 31(6) 729-737. 

Kocher, A.A., M.D. Schuster, M.J. Szabolcs, S.Takuma, D. Burkhoff, J. Wang, S. Homma, N.M. Edwards, and S. Itescu, Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling afnd improves cardiac function. Nat Med, 2001.7(4) 430-6. 

Seya et al. describe the isolation of additional resveratrol tetramers, as Vitisin A 67 with cardiomyocyte apoptosis activity (09MI90) for more dimeric resveratrols, cf. (08MI507). 

KocherAA, Schuster MJ, Szabolcs S, etal. Neovascularization of ischemic myocardium by human bone-marrow derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Medicine... 

Communal, C., and Colucd, W.S. 2005. The control of cardiomyocyte apoptosis via the 3-adrenergic signaling pathways. Arch. Mai. Coeur Vaisse 98 236-241. 

Mice that lack caspase-1, -11, or -12 do not have a significant decrease in viability and have no overt consequence on their development [57-59,69,72]. In contrast, caspase-3 and/or -9 ablation results in retarded developmental apoptosis and has a tremendous impact on animals viability and phenotype [61, 67]. Similarly, caspase-8 knockout mice die in utero and are characterized by impaired formation of cardiac muscle and marked abdominal congestion with reduction of the number of hematopoietic precursors [65], The size of the heart was reported to be almost normal, but the developing ventricular musculature was thin and sometimes similar to early mesenchyme. The trabeculae were thin and disorganized. Cultured fibroblasts from caspase-8 mice were resistant to death receptor-mediated apoptosis. These findings indicate that caspase-8 plays an important role in death induction by several receptors of Fas/TNF/NGF family. Similarly, Sakamaki et al. [66] described that protease-deficient caspase-8 mutant mice died in utero due to heart rupture which they believe was due to cardiomyocyte apoptosis. 

Studies in various animal models and in human hearts suggest that apoptosis does occur in ischemia/reperfusion injury of the heart, though the relative contribution of apoptosis in comparison with necrosis to cell loss in ischemia/ reperfusion injury is still controversial. Cardiomyocyte apoptosis was first reported by Gottlieb et al. [107], who studied the ischemia/reperfusion in rabbit hearts and found the hallmark of apoptosis in ischemic/reperfused hearts but not in the normal or ischemic-only rabbit hearts. Identification of apoptosis was based on the presence of fragmented DNA in electrophoretic gels, on in situ nick end-labeling assays, and on electron microscopy. They concluded that apoptosis may be a specific feature of reperfusion injury in cardiac myocytes. Subsequent studies have shown that apoptosis probably occurs both in ischemia and reperfusion [108], It appears that apoptosis is more prominent after ischemia followed by reperfusion than after ischemia alone [109, 110],... 

Apoptotic features have been occasionally found in other cardiac disorders in humans [128-131] and experimental models [107, 132-135]. Takemura et al. [135] studied Fas-induced cardiomyocyte apoptosis by electron microscopy, and found extensive condensation of nuclear chromatin and shriveled cytoplasm, fragmented nuclei, and apoptotic bodies. Apoptotic features correlated with positivity for TUNEL and caspase-3. A distinct morphological feature was the abundance of lipid-like structures in the cytoplasm at the early phase and high incidence of plasma membrane rupture at the later phase. Apoptotic bodies were observed to be phagocytosed by neighboring cardiomyocytes. 

Cardiomyocyte apoptosis has been demonstrated to occur months after acute MI, both in humans [113, 120, 136-138] and experimental animals [139-141]. Apoptotic rate was higher in the periinfarct region especially if persistent or recurrent ischemia was present, and lower in the remote... 

Although several potential therapeutic agents have been tested in animal models of ischemia/reperfusion heart injury with some success, nearly none of the specific antiapoptotic agents have reached the stage of clinical research [172]. The studies which have examined the effect of caspase inhibitors on ischemia/reperfusion models are summarized in Table 2. Broad-spectrum caspase inhibitors have been shown in many studies to reduce cardiomyo-cyte apoptosis, to reduce the size of MI, and to preserve heart function after MI [173-175, 178, 181]. The protective effect of caspase inhibitors can be seen when these agents are administered before or after the onset of ischemia but are most prominent when introduced before the onset of reperfusion [172, 175, 178]. Selective caspase inhibitors, on the other hand, have been reported to have varying effect they have been found to reduce cardiomyocytes apoptosis, but the infarct size remained unchanged [177, 178, 181],... 

Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res 2000 87 118-125. 

Nakatome M, Matoba R, Ogura Y, Tun Z, Iwasa M, Maeno Y, et al. Detection of cardiomyocyte apoptosis in forensic autopsy cases. Int J Legal Med 2002 116 17-21. 

Beranek JT. Further evidence of cardiomyocyte apoptosis in humoral (microvascular) rejection of human cardiac allografts. J Heart Lung Transplant 2004 23 378-379. 

Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki LM, et al. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 2001 280 H2726-H2731. 

X.L. Ma, S. Kumar, F. Gao, C.S. Louden, B.L. Lopez, T.A. Christopher, C. Wang, J.C. Lee, G.Z. Feuerstein and T.L. Yue, Inhibition of p38 mitogcn-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99(13), 1685 1691 (1999). 

P.S. Ray, J.L. Martin, E.A. Swanson, H. Otani, W.H. Dillmann and D.K. Das, Transgene overexpression of alphaB crystallin confers simultaneous protection against cardiomyocyte apoptosis and necrosis during myocardial ischemia and reperfusion, FASEBJ. 15(2), 393-402 (2001). 

Y. Ruixing, Y. Dezhai, and L. Jiaquan, Effects of cardiotrophin-1 on hemodynamics and cardiomyocyte apoptosis in rats with acute myocardial infarction, J Med Invest 51, 29-37 (2004). 

D.B. Ostrander, G.C. Sparagna, A.A. Amoscato, J.B. McMillan, and W. Dow-han. Decreased cardiolipin synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis, J. Biol. Chem., 2001, 276, 38061-38067. 

Imaging of myocardial apoptosis As mentioned above, cardiomyocyte apoptosis is a pathologic feature of heart failure. A characteristic feature of apoptosis is the exter-nahzation of phosphatidylserine phosphoh-pids [135] - a lipid that, under normal conditions, is present in only the inner layer of the cell membrane. Radiolabeled aruiex-in V, an intracellular phospholipid-binding protein, was used clinically in patients with acute myocardial infarction for the non-invasive imaging of apoptosis [136]. Moreover, the use of NIR fluorochrome-tagged annexin V has also been described [137]. 

Both LPA and SIP have vaso-regulatory functions, such as regulation of heart rate, blood pressure, platelet aggregation, and smooth muscle contraction (Karliner, 2004 Siess et al., 2000). Atherosclerosis is a type of accelerated vasculitis that reduces blood flow leading to heart attacks and strokes (Siess, 2002). It is well known that HDL level correlates with a reduced risk of cardiovascular disease, such as atherosclerosis (Choi et al., 2006), and it has been recently shown that it is the SIP content of HDL that mediates many of its effects. For example, HDL induces vasodilation and myocardial perfusion by activation of SIP3 (Levkau et al, 2004 Nofer et al., 2004). Furthermore, in an in vivo mouse study, HDL and SIP reduce the infarction size about by 20 and 40% and also inhibit inflammation caused by the recruitment of polymorphonuclear leukocytes and cardiomyocyte apoptosis via the SIP3 receptor eNOS/NO pathway (Theil-meier et al., 2006). 

Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C (2002) Doxombicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2 Bax ratio. Cancer Res 62 4592-4598... 

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