American Journal of Advanced Drug Delivery Open Access

Keywords

Ventricular remodeling, Myocardial infarction, Heart failure, Apoptosis, Cell proliferation, Necrosis, Reperfusion

Introduction

The concluding universal pathway remains as HF of various etiologies which are categorizing as reduced systolic as well as/or diastolic function through high morbidity and mortality rate. The old-style description for myocyte loss was cell death; however, concluded the preceding decade, there has been a heave of sign confirming the origin of HF through apoptosis [1]. This medium was far along deep-rooted in hearts, which remained grafted commencing patient’s end-stage HF enduring cardiac transplantation [2]. Nowadays, in human adult 50-70 billion cells tolerate apoptosis which is considered as an innovative cells in self-renewing tissue [3], Apoptosis is an essential device of cell death equally in HF and cardiac ischemia; though, the causal apparatuses through which the heart loses myocytes in HF remain entirely doubtful [4-6]. Consequently, apoptosis was steadily distinguished in MI, LVH, ischemia, ischemia-reperfusion, calcium excess, oxidative stress, gene induction, sustained stretching and doxorubicin use in investigational models of HF [7]. These studies recommend the frequency concerning the existence of apoptosis which can differ extensively as a turning point proceeding the model which is also considered the area of risk to be surveyed [8]. Acute as well as chronic disorders such as MI/reperfusion and ischemia/dilated cardiomyopathies in human and animal hearts have connected towards apoptosis [9-11]. Apoptosis can turn as a pathogenic facilitator approached a certain extent far along with cardiovascular medicine as compared to the additional fields of heart disease which has advanced explosively for the past ten years. Apoptosis set up cell suicide or cell murder in which cells will obligate suicide the minute they lack a little inbound continued existence sign in the procedure of trophic features. Otherwise, they distinguish widespread DNA damage in the identifiable nucleus. Cells will homicide new cells to attack surplus cells or else eradicate self-attacking immune cells hypothetically. Mainly in the adult tissue and the healthy tissue progression, a decisive role is played by apoptosis in the regulation of the flourishing cell inhabitants [2,12]. Apoptosis as a consequence arises from perturbations of the cell cycle. Various genes convoluted in cell cycle regulation correspondingly intricate in the management of apoptosis (e.g., c-myc, c-fos, c-jun, p53, many kinases and phosphatases) [13]. Apoptosis not only takes place afterward cell and DNA injury but then those above it’s also an imperative in embryology (ontogenesis) before to retain bodily homeostasis.

As a final point, therapeutic intermediation intended on decreasing apoptosis appeared to transform the progression of HF in addition to this; auxiliary concreted an experimental protagonist meant for apoptosis in HF progression. Entire of this experimental studies consume elevated apoptosis as of a ‘histological curiosity’ in the direction of an electrifying ‘clinical target’ that knows how to be tempered to mitigate the advancement of HF. On the other hand, no therapeutic intermediation has so far been reputable to report the problem of cardiac apoptosis, nor in attendance continually a clinical trial intended at appraising a useful method towards the issue. In the contemporary appraisal, experimental studies disparagingly evaluate the significance of apoptosis to cell death correlated to re-perfuse MI, in addition to an opportunity of beneficial anti-apoptotic intercessions [14-21]. Thus, to find out all the causes, significance and inclusive impact to inhibit HF and future allegations of apoptosis we will review the current literature along with the management of CVDs.

Types of Apoptosis

Apoptosis can be divided into three categories: Internal apoptosis, External apoptosis and Apoptosis Inducing Factor (AIF). Apoptosis may ensue from internal signals which rise from the damage of cells internally. A protein is triggered entitled BAX which makes the production of apoptosomes. Caspase is the alternative form of apoptosome which breaks down the structure of cells eventually. Similarly, apoptosis occurs from external signals in which the Fas protein is triggered in the cytoplasm and caspase-8 is activated. Also, the cell suicide caused by apoptosis-inducing factor is answerable for conducting nerve impulses. AIF is a protein in which cell receives a signal and is released into the cytoplasm. This comfort destroys the DNA due to which cell dies inevitably [22-24].

In the same way, different forms of apoptosis have been detected in animals which are as follows: Para-apoptosis a type of non-necrotic cell death regarded as reduced chromatin, cytoplasm vacuolization owing swollen mitochondria and endoplasmic reticulum (ER) [25,26].

Paraptosis a protestant form of para-apoptosis, in which cells remain TUNEL-negative; caspase-9-dependent has a morphological similarity to necrosis and topographies comparable to traditional apoptosis [27].

In Lipoapoptosis the stability of lipid metabolism is misplaced leading to a disruption in homeostasis with a build-up of fatty acids monitored by apoptosis [28].

DNA damage induced in which multinucleate huge cells are assumed to decrease via mitotic catastrophe known as Neosis [29].

Necroptosis a programmed necrosis-like death, persuaded by the necrostatin-1 (Nec-1) then connected through features of autophagy. In this procedure of death, the traditional Fas/TNF receptor family of death-domain receptor trail that chronologically shots on multiple caspase scans persuade cell death as soon as caspase signaling and consequently apoptosis is inhibited [30].

Autophagy is a further an existing mechanism and assumed to be deliberated a non-apoptotic form of cell death [31]. Other types of apoptosis are shown in Table 1.

Table 1: Classification based on the mode of cell death vs. apoptosis

The Apoptotic Process by Specific Morphological Features

The pathophysiological ground in which little contrivance and the morphology of the pretentious cell considered as cell death illustrated in Table 1 [32]. Currently, apoptosis is acknowledging as an essential device, a procedure of programmed cell death which is structured physiologically, genetically as well as shows a principal protagonist in advancement, morphogenesis, healthy cell turnover, hormone-dependent organ atrophy and immune system function [32-34]. They draw our attention as necrosis persists in mentioning the concluding stage of one or the other apoptosis as well as oncosis in which progressive deterioration exists (Figure 1).

Concerns have arisen as Apoptosis classified into three stages: induction, determination and execution [35]. Making allowance for ultra-structural alterations that proceeds in the course of apoptosis individuals in the focus which might remain even more impressive. Throughout the process of apoptosis, nuclear chromatin consistently shrinks, attributes towards the atomic film and adopts a curve, half-moon or horseshoe-like emergence (Figure 2) [32].

The summarized chromatin appears shiny as well as abruptly delineated. Cell contraction escorted using cytoplasm compression which correspondingly arises in anticipation of the cell turns out to be first multi-lobulated as well as fragmented. The nucleus remains correspondingly fragmented. However, added subcellular organelles remain full of life in morphological standing still the concluding stage. The cell fragments occur in the apoptotic forms; stay fenced using the plasma membrane that seems in one piece subsequently that the cellular stuff is unbound. Also, they are promptly phagocytized using macrophages or neighboring cells. However, apoptosis seeks out the edge to inflammation, which remains in divergence to necrosis now in which an inflammatory reaction arises in line with rupture of the plasma membrane as well as the discharge of cellular contents.

A remarkable feature of ‘necrosis’ is an average tenure defining an additional approach to cell death that varies from apoptosis. Necrosis states merely to an unalterable phase of cell death, however dying cells usually develop commencing an alterable to an unalterable stage. On the road to discourse this specific matter, Majno et al., rejuvenated an ancient term, “oncosis,” which discusses cell death conveyed by inflammation [36]. They projected in the direction of oncosis intended instead of necrosis in cells dying using a procedure comprising cellular swelling or else dropsy, as well as distinguished oncosis through apoptosis, which is complemented by cellular contraction. Both of them formerly projected that necrosis is located in the direction to mention the ultimate stage of either apoptosis or oncosis nowadays to show advanced degeneration. In the course of expansion, apoptosis subsidizes towards the normal morphogenesis of the heart, equally supports towards the morphogenesis of additional body parts. Similarly, apoptotic cardiomyocyte death remains renowned for taking place in the course of embryogenesis, even though after birth apoptosis exist to be convoluted towards the morphogenesis of the conduction scheme, as well as the sinus node, AV node and His bundle [37].

Apoptosis in Myocardial Ischemia and Infarction

Apoptosis is convoluted at many plugs in the ordinary antiquity of HF. The preliminary proceedings like ischemia, infarction and inflammation take place well ahead in distinguished LV dysfunction. Myocardial ischemia and infarction signify the first conversion to HF which was conveyed by structures etiologies that emphasize together the expansion of CHF with the typical characteristic of the cardiac heart formally. Cardiomyocyte loss secondary to extended pump dysfunction [38], myocardial fibrosis [39], as well as ischemia, consumers long term to be assumed to outcome after an apparent decline in the volume fraction of cardiac myocytes Necrosis [40]. Cell death can be categorized as the pathophysiological origin, the molecular mechanism or the morphology of an exaggerated cell. Apoptosis remains as per a morphological tenure devised by Kerr et al., in 1974 [41]. Surrounded by the numerous cardiovascular disorders (CVD), MI is predominantly remarkable intended for consuming high proportions of equally mortality and morbidity. Patients undergoing MI remain a possibility of unexpected demise in the course of the acute stage also to the time ventricular remodeling as well as HF through the chronic phase.

Additionally, extra features, comprising slow demise or hypertrophy of cardiomyocytes, fibrosis as well as the appearance of numerous cytokines, remain connected through the unrelenting disease advancement through the enduring stage. Remarkably, apoptosis remained distinguished in the HF through all phases of MI, proposing apoptosis might stay accountable intended for the noteworthy quantity of cardiomyocyte death during the acute ischemic period, as well as for a reformist forfeiture of enduring cells all through the subacute and chronic stages. Patients persisting massive MIs remain specifically in elevation risk of evolving such HF without a doubt, patients with post-infarcted HF aimed at about 44% of candidates intended for cardiac transplantation [42].

As a result, the entitled “apoptotic cardiomyocytes” in the infarcted zones remained truly irreversibly oncotic cells using fragmented DNA. Some concluding steps in the apoptotic procedure approximately stimulated in infarcted tissue, this initiation possibly has no significance towards the magnitude of infarction now which is firmed irreversibly by oncotic cardiomyocytes. Moreover, even though forfeiture of mitochondrial penetrability conversion has witnessed in the heart rendered ischemia/ reperfusion associated to cardiomyocyte apoptosis [43], the latest study repudiated that connection [44], assisting the uncertainty of cardiomyocyte apoptosis in the course of ischemia/reperfusion.

Anti-Apoptotic Therapy for Hf

Unlike necrosis, apoptosis considered to be a methodical as well as synchronized progress and possibly should remain agreeable to anticipation or else reticence if intervention takes place by an initial stage. The bound of a current investigation in this zone consumes up stretched potentials even more. On the other hand, although a quantity of prospective therapeutic mediators remained in animal models through more or less success, approximately not any of the detailed anti-apoptotic agents have stretched in the phase of the clinical investigation. Roughly the main barriers embrace the requisite intended for additional statistics nearly for the judgment of anti-apoptotic analysis the precise passage that necessary aiming as well as the mechanisms through which the body reacts to that kind of inhibition. In attendance three well-defined pathologically distinctive approaches of cell death are necrosis, apoptosis and autophagy36. In the audience, a clinicopathological indication is targeted at these three procedures of cell death in the concluding stage of cardiomyopathy [45].

Even though cardiac myocyte necrotic tissue remains the ancient hypothesized revenue of the cell death in decompensating hypertrophy prominent to cardiomyopathy, numerous illustrations remain speedily hoarding approximately in the participation of programmed cell death throughout clinical as well as an investigational exemplary of HF or else decompensatory hypertrophy [46]. Usually, apoptosis remains enormously intermittent as the normal myocardium. Merely only one apoptotic cell is noticeable among 104-105 cardiac myocytes [47]. The fraction of apoptotic cardiac myocytes raises by means of the extent of cardiac problems, such as dilated cardiomyopathy [10], hypertrophic cardiomyopathy [48], in addition to right ventricular dysplasia [49]. The coherent objective to lessen apoptotic cardiac myocytes sprightlier among the failing heart would remain electrocution caspase. Next, to this instant, broad-spectrum caspase inhibitors are now appraised in the altered clinical investigation on the way to regulate the effectiveness of them as a broad hepatoprotective medication in postponing or inhibiting the development of hepatitis leading to cirrhosis. As demonstrated above, the mainstream of pre-clinical studies anywhere in anti-apoptotic approaches were assessed practically through the drugs early in the course of the injury. Those above will develop investigation to enterprise survey where the effectiveness of anti-apoptosis treatments are verified in future platforms, as soon as animal models of HF are in further progressive periods of cardiomyopathy. A new significant concern, formerly boarding on clinical trials, is the accessibility of procedures to appraise actual myocyte loss (and protection thereof), sooner in a non-invasive manner.

Honestly, full indication facts towards the advantageous trait of caspase inhibitors are mainly trendy in acute ischemia-reperfusion-induced cardiac disorders [50]. Alongside caspase, additional cellular targets in the apoptotic trail correspondingly embrace potentials using forthcoming beneficial procedures in HF. Outsized MIs lead to chronic HF through an adverse remodeling of the left ventricle which is categorized by ventricular dilation as well as lessened cardiac performance [51]. The last mass of severe infarct that can be firmed quite a few hours later the onset [52] remains the chief precarious determining factor of the following reperfusion. Conversely, various additional features, comprising delayed cardiomyocyte death or else hypertrophy, fibrosis in addition to the appearance of several cytokines remains correspondingly connected by means of disease advancement [53,54]. Once exposed in the direction of a continuous load, the heart upholds proper efficient level from side to side cardiomyocyte hyperfunctionality and hypertrophy.

Regulation and Inhibitor of Apoptosis

An appreciative detection of apoptotic signaling now in cardiac myocytes possibly will aid in mounting beneficial clinical settings. Additionally, some of the large-scale judgment presents the treatment ability of ACE inhibitors as well as β-blockers mainly for inhibiting progression and advancement of HF after infarction, even though it is imprecise whether the advantageous effects instinctively are subject to the antiapoptosis [55]. Moreover, caspases along with cellular marks in the apoptotic trail correspondingly embrace possibilities as upcoming beneficial procedures for the cardiac disorder. Aurintricarboxylic acid (ATA) is an inhibitor that entities endonucleases and remained located moderately following apoptotic paths, also, to aggravating DNA strand breaks.ATA was lately revealed significantly to lessen some apoptotic cells precisely in the peri-necrotic myocardium of an ischemia-reperfused dog model. Simultaneously, Bcl-2 set up increased considerably, whereas Bax, as well as stimulated caspase-3, was condensed significantly [56]. As a final point, oxidative stress is communal in cardiac disease as well as it knows how to generate the ‘‘intrinsic’’ apoptotic pathways through numerous procedures comprising arise in p53, Bax as well as Bad translocation towards the mitochondria, the release of cytochrome complex and caspase activation [56,57]. From these functional boundaries, possible limitations correspondingly exist as can apoptosis remains selectively modified in a single organ or cell type deprived of antagonistic effects on additional vital structures? Offsetting apoptosis drive advantageous in the management of disorders such as HF and neurodegenerative diseases; stimulating apoptosis is, conversely, important in treating syndromes where there exists insufficient cell death, such as cancer. Invariance, these clinical benefits of TNF-α antibody on the diagnosis of acute to chronic HF remained lined out primarily by the outcomes of current clinical phases [53,54]. Autophagic cell death is known as a substitute procedure of programmed cell death that has newly concerned attention [58]. Autophagy cell death stayed mainly for eradicating apoptosis by removing redundant cells, as cells do die through autophagy. Also incurably segregated cells, similar to neurons then cardiomyocytes, remained to be even more complicated to autophagy than additional cell types [59]. A family with particular cysteine proteases known as apoptotic cell death concludes activating caspases which is an indispensable factor for the damage to the cell. Caspases indicated with large (p20) and small subunit (p10) entailing prodomain is stated as zymogens (Figure 3) [60,61]. The initiator caspases called caspase-9 and caspase-8 exist in proteolytic cascades which are started naturally where caspase-3 and caspase-7 are the downstream effector’s caspases cleaved and activated by the initiators [60,62]. Working on transgenic mice conditionally express active caspase-8 in the heart, Wencker et al., [63] initiate that deficient altitudes of chronic myocyte apoptosis remained adequate to groundwork a fatal dilated cardiomyopathy. Left ventricular dilation along with enhanced ventricular function gets prevented with a caspase inhibitor through inhibition of cell death [64-67].

Studies are correspondingly contradictory as in humans; apoptosis appears to take place predominantly in the boundary zone of the ischemic area. On the other hand, in vivo animal studies have established apoptosis equally now in the ischemic region as well as in the ischemic border zone. In divergence roughly in some studies, ischemia triggered apoptosis in the ischemic area alone [68,69]. However, HF triggered a reduction in apoptotic cells in the ischemic area and proliferation of apoptotic cells in the ischemic border zone and the distance from ischemia regions [70]. Through complex signal transduction, apoptosis takes place through the initiation of the death receptor trail (known as extrinsic path) prominent to stimulation of caspase cascade from the plasma membrane. The death receptors fit the carcinoma or sarcoma necrosis receptor superfamily which remains as transmembrane proteins through an extracellular ligand-interacting domain, called transmembrane area as well as an intracellular death domain. The central apoptotic pathways intricated includes the death receptor, the mitochondrial and ERstress significantly in the heart tissue. A diagrammatical view of apoptotic cascades is shown in (Figure 4) [66,71-73].

Amusingly, current findings recommend that among autophagy and apoptosis a cross-talk is apprehended. Anti-apoptotic Bcl-2 family members along with pro-apoptotic BH3-only proteins can take part in the inhibition and induction of autophagy, correspondingly. Close by information that cross-talk has been induced among the death receptor pathway along with ER-stress pathway [74,75]. For illustration, management of L929 cells using the Fas L-induced processing of caspase-12 along with the stimulation of caspases-3, -7 and -9 started [76,77]. Stimulation of caspase-8as, a result of death receptor trail, openly stimulates executioner caspase-3, however, splits the BH3-only protein Bid next to aspartate 60 to engender a 15 kDa condensed form (tBid) that simplifies discharge of cytochrome complex after the mitochondria [78-80]. Also, caspase-8 remained stimulated and Bid stayed separated to t-Bid, advising simultaneous stimulation of mutually the death receptor as well as mitochondrial death trails in the heart through TNF-a. In the provision of this, Bcl-2 overexpression merely partly mitigated cardiomyocyte apoptosis also not affecting extrinsic signaling [81-83].

Conclusion

Referring backward and forwards ten years have proceeded as per the first explanation of apoptosis mainly in MI; this subject matter endures to fascinate considerably more devotion. The severe utmost issue possibly will detect cardiomyocyte apoptosis in prophylactic hearts, which restrains its anticipation through any stage of MI. An apparent fact is that apoptosis shows a crucial part in the pathogenesis of numerous CVDs. Apoptotic trails (death receptor, mitochondrial and ER stress), are acknowledged in the heart mainly to subsidize myocyte damage in multiple CVDs. Apoptosis is considered as an active target for beneficial intervention as it is an extremely structured process. Similarly, using novel study findings comprising transgenic mice, gene deletion, recombinant proteins and pharmacological inhibitors of cardiac myocyte apoptosis outcomes in cardio-protection along with inhibition of HF. Possibly as apoptosis is well-thought-out to be further controllable than necrosis, not merely due to its systematic consequence but also due to the probability of a beneficial presentation which energies investigation on the subject matter. An in-depth indulgent of multifaceted mechanisms related to cardiac myocyte apoptosis is imperative to classify prospective aims as well as to progress novel therapeutic approaches for CVD. We accomplish from our study that there occurred numerous foot race to prevail beforehand regulation of apoptosis which can remain clinically used in the management of MI and HF in addition to; inhibiting apoptosis is an anticipated endpoint.

Acknowledgments

We acknowledge the service and directions from the School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, School of Pharmacy. Also, we profoundly thank the Chinese Scholarship council PR China for funding our postgraduate studies.

Conflict of Interest

All authors declare there is no conflict of interest regarding the content of this article.

References

1. Thompson KA. Heart failure therapy: Beyond the guidelines. J Cardiovasc Med. 2010;11(12):919-927.
2. Gajarsa JJ, Kloner RA. Left ventricular remodeling in the post-infarction heart: A review of cellular, molecular mechanisms and therapeutic modalities. Heart Fail Rev. 2011;16(1):13-21.
3. Debatin KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother. 2004;53(3):153-159.
4. Lee YJ, Jeong SY, Karbowski M, et al. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004;15(11):5001-5011.
5. Cassidy-Stone A, Chipuk JE, Ingerman E, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14(2):193-204.
6. Zanna C1, Ghelli A, Porcelli AM, et al, OPA1 mutations associated with dominant optic atrophy impairs oxidative phosphorylation and mitochondrial fusion. Brain. 2008;131(Pt 2):352-367.
7. Rathmell JP. The Link between acute and chronic Pain. Review Course Lectures. 2012;42.
8. Yue TL, Ohlstein EH, Ruffolo RR. Apoptosis: A potential target for discovering novel therapies for cardiovascular diseases. Cur Opin Chem Biol. 1999;3(4):474-480.
9. Ky B, French B, McCloskey K, et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail. 2011;4(2):180-187.
10. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 1996;335(16):1182-1189.
11. Javadov S, Choi A, Rajapurohitam V, et al. NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res. 2008;77(2):416-424.
12. Matturri L, Milei J, Grana DR, et al. Characterization of myocardial hypertrophy by DNA content, PCNA expression and apoptotic index. Int J Cardiol. 2002;82(1):33-39.
13. Jarpe MB, Widmann C, Knall C, et al. Anti-apoptotic versus pro-apoptotic signal transduction: Checkpoints and stop signs along the road to death. Oncogene. 1998;17(11):1475-1482.
14. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456-1462.
15. Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res. 1994;75(3):426-433.
16. Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74(1):86-107.
17. Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996;148(1):141-149.
18. Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 1994;94(4):1621-1628.
19. Hamet P, Richard L, Dam TV, et al. Apoptosis in target organs of hypertension. Hypertension. 1995;26(4):642-648.
20. Liu Y, Cigola E, Cheng W, et al. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest. 1995;73(6):771-787.
21. Cheng W, B Li, J Kajstura, et al. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995;96(5):2247-2259.
22. Phaneuf S, Leeuwenburgh C. Apoptosis and exercise. Med Sci Sports Exerc. 2001;33(3):393-6.
23. Nikoletopoulou V, Markaki M, Palikaras K, et al. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta. 2013;1833(12):3448-3459.
24. Rongvaux A, Jackson R, Harman CC, et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014;159(7):1563-1577.
25. Galluzzi L, Bravo-San Pedro JM, Vitale I, et al. Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015. Cell Death Differ. 2015;22(1):58-73.
26. Kasuba KC, Vavilala SL, D'Souza JS. Apoptosis-like cell death in unicellular photosynthetic organisms: A review. Algal Research. 2015;12:126-133.
27. Bröker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: A review. Clin Cancer Res. 2005;11(9):3155-3162.
28. Pohle T, Brändlein S, Ruoff N, et al. Lipoptosis: Tumor-specific cell death by antibody-induced intracellular lipid accumulation. Cancer Res. 2004;64(11):3900-3906.
29. Sundaram M, Guernsey DL, Rajaraman MM, et al. Neosis: A novel type of cell division in cancer. Cancer Biol Ther. 2004;3(2):207-218.
30. Matsumura H, Shimizu Y, Ohsawa Y, et al. Necrotic death pathway in Fas receptor signaling. J Cell Biol. 2000;151(6):1247-1256.
31. Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. J Pathol. 2010;221(1):3-12
32. Takemura G, Fujiwara H. Morphological aspects of apoptosis in heart diseases. J Cell Mol Med. 2006;10(1):56-75.
33. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284(5756):555-556.
34. Cohen JJ. Programmed cell death in the immune system. Adv Immunol. 1991;50:55-85.
35. Tanuma S. Molecular mechanisms of apoptosis. Apoptosis in normal development and cancer. 1996:39-59.
36. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146(1):3-15.
37. James TN. Normal and abnormal consequences of apoptosis in the human heart: From postnatal morphogenesis to paroxysmal arrhythmias. Trans Am Clin Climatol Assoc. 1994;105:145-178.
38. Mirsky I, Pfeffer JM, Pfeffer MA, et al. The contractile state as the major determinant in the evolution of left ventricular dysfunction in the spontaneously hypertensive rat. Circ Res. 1983;53(6):767-778.
39. Bing OHL, Sen S, Conrad CH, et al. Myocardial function structure and collagen in the spontaneously hypertensive rat: Progression from compensated hypertrophy to haemodynamic impairment. European Heart Journal. 1984;5(suppl_F):43-52.
40. Conrad CH, Brooks WW, Hayes JA, et al. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation. 1995;91(1):161-170.
41. Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994;73(8):2013-2026.
42. Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: Seventeenth official report-2000. J Heart Lung Transplant. 2000;19(10):9099-9131.
43. Borutaite V, Jekabsone A, Morkuniene R, et al. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J Mol Cell Cardiol. 2003;35(4):357-366.
44. Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005;434(7033):652-658.
45. Schaper J, Froede R, Hein S, et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation. 1991;83(2):504-514.
46. Elsasser A, Suzuki K, Schaper J. Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure. J Mol Cell Cardiol. 2000;32(5):711-724.
47. Soonpaa MH, Field LJ. Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res. 1998;83(1):15-26.
48. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart. Circulation. 2003;107(7):984-991.
49. Mallat Z, Tedgui A, Fontaliran F, et al. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med. 1996;335(16):1190-1197.
50. Yaoita H, Ogawa K, Maehara K, et al. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation. 1998;97(3):276-281.
51. Pfeffer MA. Left ventricular remodeling after acute myocardial infarction. Annu Rev Med. 1995;46:455-66.
52. Reimer KA, Vander Heide RS, Richard VJ. Reperfusion in acute myocardial infarction: Effect of timing and modulating factors in experimental models. Am J Cardiol. 1993;72(19):13G-21G.
53. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure. Circulation. 2003;107(25):3133-3140.
54. Mann DL, McMurray JJ, Packer M, et al. Targeted anti-cytokine therapy in patients with chronic heart failure. Circulation. 2004;109(13):1594-1602.
55. Swedberg K, Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol. 1988;62(2):60A-66A.
56. Li Z, Zhang T, Dai H, et al. Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. J Clin Biochem Nutr. 2007;41(1):58-67.
57. Zhu H, Tannous P, Johnstone JL, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. The J Clin Invest. 2007;117(7):1782-1793.
58. Lockshin RA, Zakeri Z. Caspase-independent cell deaths. Curr Opin Cell Biol. 2002;14(6):727-733.
59. Larsen KE, Sulzer D. Autophagy in neurons: A review. Histol Histopathol. 2002;17(3):897-908.
60. Silke, J, Meier P. Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol. 2013;5(2):pii:a008730.
61. Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 2004;5(11):897-907.
62. Berger AB, Witte MD, Denault JB, et al. Identification of early intermediates of caspase activation using selective inhibitors and activity-based probes. Mol Cell. 2006;23(4):509-21.
63. Wencker D, Chandra M, Nguyen K, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003;111(10):1497-504.
64. Song Y, Wang J, Li Y, et al. Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury. Am J Pathol. 2005;167(1):17-26.
65. Thorburn A. Death receptor-induced cell killing. Cell Signal. 2004;16(2):139-44.
66. Liao X, Wang X, Gu Y, et al. Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis. Life Sci. 2005;77(2):160-74.
67. Clarke MC, et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res. 2008;102(12):1529-38.
68. Abbate A, Melfi R, Patti G, et al. Apoptosis in recent myocardial infarction. Clin Ter. 2000;151(4):247-51.
69. Olivetti G, Quaini F, Sala R, et al., Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996 Sep;28(9):2005-16.
70. Palojoki E, Saraste A, Eriksson A, et al. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2001;280(6):H2726-31.
71. Gilles S, Zahler S, Welsch U, et al. Release of TNF-α during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers. Cardiovascular Research. 2003;60(3):608-616.
72. Lee P, Sata M, Lefer DJ, et al. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo. Am J Physiol Heart Circ Physiol. 2003;284(2):H456-63.
73. Lee Y, Gustafsson AB. Role of apoptosis in cardiovascular disease. Apoptosis. 2009;14(4):536-548.
74. Maiuri MC, Criollo A, Tasdemir E, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-XL. Autophagy. 2007;3(4):374-376.
75. Rashmi R, Pillai SG, Vijayalingam S, et al. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene. 2008;27(10):1366-1375.
76. Nickson P, Toth A, Erhardt P. PUMA is critical for neonatal cardiomyocyte apoptosis induced by endoplasmic reticulum stress. Cardiovascular Res. 2007;73(1):48-56.
77. Kalai M, Lamkanfi M, Denecker G, et al. Regulation of the expression and processing of caspase-12. J Cell Biol. 2003;162(3):457-467.
78. Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of end Science. 2003 Apr 4;300(5616):135-9. Epub 2003 Mar 6. oplasmic reticulum Ca2+: A control point for apoptosis. Science. 2003;300(5616):135-139.
79. Date T, Mochizuki S, Belanger AJ, et al. Differential effects of membrane and soluble Fas ligand on cardiomyocytes: Role in ischemia/reperfusion injury. J Mol Cell Cardiol. 2003;35(7):811-21.
80. Gyan E, Frisan E, Beyne-Rauzy O, et al. Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum. Leukemia. 2008;22(10):1864-1873.
81. Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007;30:100(6):914-922.
82. Akar U, Chaves-Reyez A, Barria M, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy. 2008;4(5):669-679.