There is an established link between depression and myocardial infarction in morbidity; however, the mechanisms underpinning this association are not comprehensively elucidated [36
]. In this study, we demonstrated the behavioral phenotype of depression after myocardial infarction, characterized by lower scores of horizontal movements, vertical movements and reduced consumption of sucrose solution, in the depression and post-MI depression rats. These are models of lowered emotional activity and exploratory behavior, where the post-MI depression group demonstrated altered reward preference.
Apoptosis is an ordered, active, non-inflammatory process of cell death caused by a pathological or physiological stimulation of a genetically mediated regulatory system. Previous studies have demonstrated that in ischemia and reperfusion damage, apoptosis in the myocardium plays a role in the pathology of heart diseases, including myocardial infarction and dilated cardiomyopathy [21
]. Cardiomyocyte apoptosis is a key form of cell death, and apoptotic cell death plays an important role in the development of heart failure [38
There are two major apoptotic pathways in mammalian cells, ''intrinsic'' and ''extrinsic''. Both kinds of apoptotic pathways were observed simultaneously in the experiment secondary to activation and non-activation of caspase-3, which may cause cleavage of substrates and cell death. The mitochondrial-mediated pathway of apoptosis is regulated by the Bcl-2 family of antiapoptotic (Bcl-2, Bcl-xl, Mcl-1) and proapoptotic proteins (Bax, Bad and Bak), and Bcl-2 inhibits apoptosis by interacting and forming inactivating heterodimers with Bax/Bak. It has been suggested that the Bax/Bcl-2 ratio may be more important than either promoter alone in determining apoptosis. The Bax/Bcl-2 ratio is a measure of a cell's vulnerability to apoptosis; therefore, in our study, the use of a more sensitive, Bax/Bcl-2 ratio predominantly reflected apoptosis. In myocytes, the 'intrinsic'' pathway is primarily activated when cells are stimulated by hypoxia, ischemia-reperfusion and oxidative stress [26
]. Oxidative stress has been hypothesized in part to mediate the link between somatic and psychiatric disorders [39
]. Cardiac dysfunction and heart failure are documented after acute emotional stress [40
]. The pathway of apoptosis is influenced by the Bax/Bcl-2 ratio and activated caspase-3. A high Bax/Bcl-2 ratio is associated with greater vulnerability to apoptotic activation, while a high caspase-3 level is often associated with apoptotic activity.
We observed that there was an increased myocardial Bax:Bcl-2 ratio in the depression, MI and post-MI depression groups, this was particularly so in the latter group, where there was a greater Bax:Bcl-2 ratio which is important in determining a cell's vulnerability to apoptosis. Up-regulation of the Bax/Bcl-2 ratio can induce greater apoptotic activity [16
], suggesting that there was greater vulnerability to apoptosis of myocardial cells with acute myocardial infarction with comorbid major depression. These data suggest that post-MI depression can activate pro-apopotic pathways; however, the regulatory mechanisms underlying apoptosis in the myocardium remain unclear.
This study also demonstrated that the up-regulated Bax/Bcl-2 ratio may modulate apoptosis associated with progression of the disease [41
]. The Bax/Bcl-2 ratio may serve as an independent predictive marker of the therapeutic response [42
], and merits further examination, as the myocardial infarction with depression induced increase of the Bax/Bcl-2 ratio might enhance apoptosis of cardiomyocyte [43
]. These data suggest that depression after myocardial infarction may increase the Bax/Bcl-2 ratio and induce further cardiomyocyte apoptosis, which may play an important role in the higher morbidity after myocardial infarction in conjunction with depression.
Contrary to hypotheses, we found no difference in caspase-3 in the myocardium of the post-MI depression group versus the MI, depression and sham groups. This may indicate that caspase-3 is not an active pathway to apoptosis in the myocardium in the model of myocardial infarction with depression. In interpreting this, several factors should be considered. First, caspase-3 may not be activated during the post-MI depression. It is possible that caspase-3 activity was low because the apoptotic process in the myocardium was only finished two weeks post-MI. Second, it is possible that caspase-3 activity may induce apoptosis via another independent pathway. Third, the up-regulated Bax/Bcl-2 ratio may decrease the cell's viability in involving other effector caspases without the activity of caspase-3 [16
]. Other caspases may be involved. Lancel et al
] showed that endotoxin induced increases in ventricular cardiomyocyte caspase-3, -8 and -9-like activities. This was associated with sarcomeric structure damage and cleavage of components of the cardiac myofilament. Frantz et al
] noted that rats with deletion of the caspase-1 gene showed increased peri-infarct survival and a lower rate of ventricular dilatation and a decreased rate of apoptosis after a model of myocardial infarction.
However, we did not find a relationship between other caspases and the model of MI with depression. Apoptotic pathways may interact with other pathways of shared risk including ischemia and reperfusion damage, inflammatory and oxidative pathways [38
] and other non-specific mechanisms, suggesting the need for further exploration of these interactions.
In this study, we found a depressive-analog anhedonia-like state in rats after myocardial infarction. These changes have parallels with the core symptoms of depression. There may be a mechanistic association with the up-regulation of the Bax/Bcl-2 ratio in the myocardium after myocardial infarction with depression. Our study demonstrated that in rats with post-MI depression, there is an increase in pro-apoptotic pathways in myocardium after myocardial infarction. Cardiomyocyte apoptosis is a key form of cell death, and apoptotic cell death plays an important role in the development of heart failure [38
], resulting in a decreased heart function and reduced cardiac output.
There are certain limitations that need to be kept in mind when interpreting these data. First, our previous study demonstrated that in rats with chronic mild stress, there is an increase in pro-apoptotic pathways in the myocardium and hippocampus after depression, which was reversed by venlafaxine. To extend this line of study, our purpose was to attempt to evaluate myocardial apoptosis after myocardial infarction with depression, to clarify the molecular mechanisms, as well as confirm whether the higher incidence of myocardial infarction with depression is associated with apoptosis pathways, so the use of an inhibitor of apoptosis after myocardial infarction may further clarify the role of apoptosis. Similarly, the use of a chronic unpredictable stress-depressed (depression) group on which surgery is performed as another "control" group could have assisted interpretation of these results. Second, in our experiment, only 7 out of 20 myocardial infarction rats developed an anhedonic-like state compared to sham and depression groups; this pattern differs from reports by other groups and may be related to methodological variance. Third, it would also have been helpful for the sucrose test to have been done weekly in addition to baseline and endpoint readings. Further experimentation will clarify this point. In addition, although our results showed no effect of caspase-3 level in the myocardium after myocardial infarction and depression, it may induce apoptosis via an independent caspase-3 pathway, or other caspases expressed in the heart, suggesting again the need for further study.