Captopril was the first orally effective angiotensin-converting enzyme inhibitor, and since its approval by the FDA in 1981 for the treatment of hypertension, it has achieved good efficacy in the treatment of congestive heart failure, ventricular remodeling after myocardial infarction, and diabetic nephropathy. It has the widest range of applications among angiotensin-converting enzyme inhibitors [1]. With the rapid development of related basic science and the in-depth research on the pharmacological effects of captopril, it has recently been found in a large number of animal and clinical experiments that captopril has both inhibitory and apoptosis-inducing effects [2-7], and this paper adopts the method of literature review to review the effects of captopril intervention on apoptosis and related mechanisms.
1. Pharmacological effects of captopril
Captopril is an angiotensin-converting enzyme inhibitor containing sulfhydryl group (SH), which not only has other pharmacological effects of angiotensin-converting enzyme inhibitors: (1) blocking the production and action of angiotensin II (AngII); (2) preserving the activity of bradykinin; (3) protecting vascular endothelial cells and antiatherosclerotic effects; (4) anti-myocardial ischemia and myocardial protective effects; (5) increase insulin sensitivity in diabetic patients; (6) prevent cardiovascular pathological remodeling, and can play a role in stabilizing mitochondrial membranes by scavenging oxygen free radicals through the sulfhydryl groups contained, inhibiting lipid peroxidation reactions [8], in addition to the immunological effect of captopril to inhibit the production of cytokines such as tumor necrosis factor and interleukins by mononuclear macrophages [9].
2. Apoptosis
2.1 The concept of apoptosis and its gene regulation
Apoptosis is the process of ending the life of a cell under certain physiological and pathological conditions by following its own program through the initiation of internal mechanisms, mainly the activation of endogenous DNA endonucleases. current studies have shown that apoptosis is a special form of cell death regulated by genes, and its regulatory genes can be divided into pro-apoptotic genes, including wild-type P53, c-myc, c-fas, c Since the concept of apoptosis was first proposed by Kerr [10] and others in 1972, apoptosis has been a major issue in recent medical science,
Since the concept of apoptosis was first introduced by Kerr [10] in 1972, apoptosis has been a hot topic of research in the medical field in recent years.
2.2 Pathways of apoptosis
The death receptors belong to the tumor factor receptor (TNFR) superfamily, including Fas, TNFR1, DR3, DR4 and DR5, and contain a death domain (DD) in the intracellular part, which recruits downstream apoptotic proteins. Once bound to the ligand of the trimer, Fas recruits the cytoplasmic bridging protein FADD through an interaction between the DD of the intracellular segment and the DD of the carboxyl terminus of FADD, which contains a DED at the amino terminus of FADD, and this DED interacts with the DED of the Caspase-8 prodomain to recruit Caspase-8 to the Fas region. Caspase-8 has a weak protein hydrolytic activity, and in DISC Caspase-8 is activated by self-shearing due to increased oligomerization hydrolytic activity.
. Activated Caspase-8 is released into the cytoplasm that activates Caspase-3, causing apoptosis; the other is the mitochondrial pathway [12]: the mitochondrial pathway [2]: various pro-apoptotic signals such as DNA damage and growth factor removal induce mitochondria to release cytochrome C. In the presence of ATP/dATP, cytochrome C binds to the WD40 repeat region of Apaf-1, prompting Apaf-1 oligomerization to form the Apaf-1-supracellular pigment C multimerization complex. This complex recruits cytoplasmic caspase-9 in a 1:1 ratio through a protein-protein interaction between the CARD at the amino terminus of Apaf-1 and the CARD of the caspase-9 prodomain. Caspase-9 acts as an initiating cysteine protease and activates downstream caspase-3 to promote apoptosis.
3. Captopril inhibits apoptosis
3.1 Captopril inhibits AngII-induced apoptosis
AngII has an important effect on apoptosis, but the mechanism of action is complex and different cells show different effects: it can cause both apoptosis and cell proliferation [13], which is mainly related to the biological effects exerted by the binding of AngII and its corresponding receptors AT1, AT2. Goldenberg I [14] and other experiments found that AngII and its corresponding receptors AT1, AT2 Goldenberg I [14] found that AngII and its corresponding receptors AT1 and AT2 combined to increase the expression of AT1 and AT2 receptor proteins and significantly upregulate the expression of pro-apoptotic genes, thus activating caspase-3 and leading to apoptosis. However, it has also been shown that AT1 receptors and AT2 receptors bind to AngII and exert opposite effects: i.e., AT1 receptors bind to AngII to promote cell proliferation; AT2 receptors bind to AngII to induce apoptosis [15]. This is consistent with the results within the experiment of Liangxuguo [16] et al. who applied captopril and cloxacin to intervene in vascular endothelial cell apoptosis induced by AngII: cloxacin, as an AT1 receptor antagonist, blocked the binding of AngII to AT1 but had no effect on cell regulation induced by AngII, thus indicating that AT1 receptors have no significant role in AngII-induced cell In contrast, the use of captopril partially inhibited AngII-induced apoptosis in vascular endothelial cells. The possible mechanism is that captopril prevented the conversion of AngI to AngII by inhibiting angiotensin-converting enzyme activity, thus not only reducing the oxygen free radicals and inflammatory mediators produced by AngII, but also partially blocking the binding of AngII to its corresponding receptor to The effect of AngII binding to its corresponding receptor on apoptosis was partially blocked. It also reduces the expression of pro-apoptotic genes and upregulates the expression of anti-apoptotic gene Bcl-2, exerting anti-apoptotic effects at the molecular level [17]. It is also related to the ability of captopril to reduce the degradation of bradykinin and increase the secretion of NO [18].
3, 2 Captopril inhibits oxygen radical-induced apoptosis
Oxygen radicals can induce apoptosis through various pathways such as direct damage to DNA, attacking proteins containing enzymatic activity, affecting nuclear gene transcription, and triggering lipid peroxidation reactions. This has been demonstrated in numerous experiments. It has also been demonstrated that intervention of oxygen radical-induced apoptosis with antioxidants or oxygen radical scavengers can prevent the activation of P53. Downregulation, BAX expression and reduction of Caspase-3 activity inhibit apoptosis [19]. And captopril itself contains sulfhydryl (SH), which not only has the effect of inhibiting microsomal lipid peroxidation reaction and leukocyte production of oxygen self radicals, but also is a powerful scavenger of oxygen radicals itself [20].Tambd [21] et al. found that captopril has a significant inhibitory effect on apoptosis caused by the production of oxygen radicals during ischemia-reperfusion, which is consistent with our scholars Hu Qingsong et al [ 22-23] and other studies found that captopril has the ability to inhibit hydroxyl radical-induced apoptosis in vascular endothelial cells and myocardium. Thus, it can be seen that captopril prevents oxygen radicals from oxidizing thiols on PT pores and stimulating PT pore opening by the dual effect of inhibition and scavenging oxygen radicals, while the sulfhydryl group (SH) contained in captopril can keep PT pores in a closed state [24], which stabilizes the mitochondrial membrane potential and prevents the release of Cyt-C and apoptosis-inducing factor (AIF) from mitochondria, blocking the mitochondrial pathway, thus inhibiting apoptosis. At the same time, captopril has a regulatory effect on the elevated proton pumping rate and electron transfer rate of mitochondrial complex II-III, which makes the proton coupling tighter, thus protecting the respiratory function of mitochondria, improving the energy metabolism of cells [25] and effectively preventing intracellular calcium overload caused by oxygen free radicals.
3.3 Captopril inhibits apoptosis by preventing bradykinin degradation
Experiments have demonstrated that captopril can increase nitric oxide (NO) production by reducing the degradation of bradykinin, so that the increased bradykinin activates phosphodiesterase C (PLC) through binding to its β2 receptor, and the resulting IP3 causes intracellular Ca2+ release and nitric oxide synthase (NOS) and upregulation of ecNOS [26].NO has a dual effect on cells, i.e., in mediating apoptosis through the production of oxygen NO has a dual effect on cells, i.e., while mediating apoptosis through the production of oxygen radicals, it can produce anti-apoptotic effects by inhibiting Caspasease enzyme activity, and the outcome of the effect is dependent on the cell type and the amount of NO [27].Experiments by Dimmelers [18] and others have demonstrated that NO can block AngII-induced apoptosis by inhibiting Caspase enzyme activity, but experiments by Fukuok [28] and others found that NO can mediate apoptosis by upregulating the expression of Fas and Bax. Therefore, we can suggest that captopril may exert anti-apoptotic effects by increasing NO levels appropriately on the one hand and scavenging oxygen radicals generated by excess NO through its sulfhydryl group (SH) on the other hand. In addition, the bradykinin-NO pathway can activate protein kinase C, reduce cellular metabolic levels, decrease ATP and oxygen demand, improve cellular energy metabolism, and prevent apoptosis [29].
3,4 Other
Recent studies have found that captopril blocks apoptosis mediated by Fas receptors: studies by UhalBD [4] and others found that captopril inhibits apoptosis by decreasing the expression of Fas and its ligand (Fasl) on the surface of alveolar epithelial cells. Furthermore Odakac Mizuochi T [30] et al. demonstrated that captopril inhibits apoptosis by interfering with the interaction between Fas and Fasl on the surface of peripheral T cells and decreases the activity of Caspase-3 analogs produced during apoptosis. This opens a new way for us to study the application of captopril in autoimmune diseases.
4.Captopril induces apoptosis
It has been demonstrated that captopril has the effect of promoting apoptosis, Buemi M [5] et al. found that captopril 0,23 mg can cause an increase in the number of apoptotic cells in vascular smooth muscle cells in experiments, and similarly Anne Mette [6] and other animal models found that captopril inhibits the proliferative stenosis of the endothelium after injury by inducing apoptosis in vascular smooth muscle cells. The exact mechanism of this is unclear and may be the result of the fact that captopril decreases the mRNA expression of the AT1 receptor for AngII in the intima after myocardial infarction [31], thus causing a diminished proliferative and anti-apoptotic effect due to the junction of AngII with AT1 and an enhanced apoptotic effect due to the binding to the AT2 receptor [32-33]. In addition, Ohwada T[34] found that treatment with angiotensin-converting enzyme inhibitors after vascular strain in rats not only significantly increased the expression of ecNOS in the neointima, but also upregulated the expression of iNOS, resulting in excessive NO production, which induced apoptosis in smooth muscle cells by upregulating the expression of Fas and Bax and downregulating the expression of Bcl-2[28] . . Recently, Glzzerman I[7] and others have successfully applied ACEI in the treatment of erythrocytosis in patients after renal transplantation and elucidated that the mechanism of action is that ACEI induces an increase in the mRNA expression of Fas and its junction protein FADD in patients after renal transplantation and upregulates its protein expression, but has no effect on the expression of BCL-2, Bcl-xl, Bax, caspase-8, caspase-3, and Bcl-xl. -8 and caspase-3, thereby inducing apoptosis of progenitor erythrocytes through activation of the death receptor pathway. Thus, the apoptosis-promoting effect of captopril is undoubtedly beneficial for the treatment of intimal hyperplasia and restenosis after coronary artery surgery, and also provides a new theoretical basis for its treatment of IgA nephropathy and diabetic nephropathy.
Problems and outlook
In summary, captopril has the dual effect of inhibiting and inducing apoptosis. However, the question at hand is why captopril produces two distinct pharmacological effects. We speculate that this depends mainly on the cell type, the dose of captopril and the pathological state of the organism, but the exact mechanism needs to be further investigated. In conclusion, there is a consensus on the role of captopril in interfering with apoptosis: captopril inhibits or promotes apoptosis by blocking the interaction between AngII and its receptor, reducing the production of oxygen free radicals, regulating NO synthesis, and interfering with the interaction between Fas and Fasl to activate or block the apoptotic program. We have reason to believe that the in-depth study of the anti-apoptotic effect of captopril will undoubtedly bring a breakthrough in the investigation of congestive heart failure, ischemia-reperfusion injury and restenosis of coronary arteries after atherosclerosis and surgery, and may promote the development of diagnosis and treatment of cardiovascular diseases.