Apoptotic cardiomyocytes

Apoptosis has been demonstrated to occur also in human MI. Studies of heart tissue obtained at autopsies from patients, who died of MI, suggest that apoptotic cardiomyocytes were most prominent in the border zones of MI (Fig. 1A and B) [111-123], whereas few were present in the remote myocardium [113, 114, 118-121]. The most commonly used method for detection of apoptosis in these studies was TUNEL. Using this method, a highly variable apoptotic rate was found, ranging from 0.8% [114] to 43% [118] in the border zone of MI, and from 0.05% [114] to 38% [118] in the remote myocardium. Using immunohistochemistry for activated (cleaved) caspase-3, a much lower apoptotic rate was reported in human MI [123]. 

It is controversial whether apoptotic cardiomyocytes in human MI exhibit characteristic morphological features such as cell shrinkage, condensation of chromatin, and fragmentation into apoptotic bodies [18]. It is also unknown how an apoptotic cardiomyocyte is released from the tight connection... 

Despite extensive research, many aspects of cell death including the molecular regulatory mechanisms, as well as the relative contribution of apoptosis and necrosis, and possibly other types of cell death to cardiomyocyte loss remain to be elucidated. An important unresolved issue is also the identification of apoptotic cardiomyocytes. 

Klepamik K, Horky M (2003) Detection of DNA fragmentation in a single apoptotic cardiomyocyte by electrophoresis on a microfluidic device. Electrophoresis 24 3778-3783... 

JNK-1 and c-fos proteins were significantly induced in the ischaemic/reperfused Langendorff rat heart, which was inhibited by a proanthocyanidin extract (Sato et al. 2001). In concert, red grape seed proanthocyanidin water-alcohol extract significantly reduced the appearance of reactive oxygen species and apoptotic cardiomyocytes in the is-chaemic/reperfused hearts. 

Hearts from red wine proanthocyanidin-fed rats were more resistant to ischemia-reperfusion injury than hearts from control animals [114, 115]. Blood flow parameters were improved, whereas infarct size, formation of hydroxyl radicals, and malondialdehyde levels of heart perfusate were all modulated as a result of feeding animals proanthocyanidins or proanthocyanidin-containing ingredients. These same dietary treatments also reduced the levels of proapoptotic factors INK and c-Jun, as well as the proportion of apoptotic cardiomyocytes. 

Grishko, V., Pastukh, V., Solodushko, V., Gillespie, M., Azuma, J., and Schaffer, S. 2003. Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes Role of DNA damage. Am. J. Physiol. 285 H2364-2372. 

It remains to be determined why apoptotic features are rarely, if ever, found in MI. It is possible that in acute MI, cardiomyocytes begin to die from apoptotic mechanism, but as cellular energy declines the cells continue to die of necrosis [22,23]. Another possibility is that complex and large cells such as cardiomyocytes may not be able to show the classical morphological characteristics of apoptosis as originally described by Wyllie et al. [6], despite the activation of the cell death program [124]. 

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... 

Maruyama R, Takemura G, Aoyama T, Hayakawa K, Koda M, Kawase Y, et al. Dynamic process of apoptosis in adult rat cardiomyocytes analyzed using 48-hour videomicroscopy and electron microscopy Beating and rate are associated with the apoptotic process. Am J Pathol 2001 159 863-891. 

At a cellular level, the purported sorafenib editors should be assayed using the renal cancer cell line RCC-786-O and NRVMs (neonatal rat ventricular monocytes). In RCCs, the sorafenib/WBZ 4 combination yields agonistic synergy, marked by an increased inhibition of cell proliferation when compared to sorafenib-alone levels at equivalent bulk concentrations (Fig. 12.5a) The dose-dependent inhibition is greater than the Loewe-additive values [20, 21] (Fig. 12.5b). By contrast, the sorafenib-induced recruitment of the pro-apoptotic pathway in cardiomyocytes should be impaired by the downstream interference of WBZ 4 through JNK inhibition (Fig. 12.3a). Consequently, cytosolic release of... 

Fig. 12.6 Network level analysis of the proposed editing therapy involving imatinib/WBZ 4 combination treatment. In the CML cells imatinib and WBZ 4 overlap therapeutically by inhibiting common clinically relevant targets PDGFR and KIT, whereas in cardiomyocytes, the inhibitory action of WBZ 4 on JNK antagonizes the pro-apoptotic pathways activated by upstream inhibition of ABL by imatinib. Reprinted from [32], copyright 2009 with permission from Elsevier...

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