Cardiovascular disease is an important and urgent public health problem worldwide, leading to kinds of comorbidities and even mortality. The prevalence and mortality of cardiovascular diseases intend to decrease in Europe and the United States, but is still rising in China. In recent years, epidemiological data shows that cardiovascular disease is the leading cause of disease death in China, even higher than tumors and other diseases. Cardiovascular mortality varies between urban and rural areas, for example: 44.8% in rural areas and 41.9% in urban areas. Therefore, it is imperative to investigate the pathogenesis of cardiovascular disease and to identify the targets for prevention and treatment of cardiovascular disease, and further research is needed.
In recent years, bioactive peptides attracted increasing attention in preventing and treating cardiovascular diseases. Cortistatin (CST) is a novel small molecule bioactive peptide containing an FWKT (Phe-Trp-Lys-Thr) tetramer. It was once thought that CST was only expressed in the brain (cortex and hippocampus, etc.). However, as the research progressed, CST was found to be widely expressed in the nervous system, endocrine system and immune system. In recent years, CST was also found in the cardiovascular system, such as the aorta, coronary arteries and heart. CST contains an FWKT tetramer that is highly homologous to somatostatin (SST). Thus, CST could activate SST receptors (SSTRs) to exert similar biological effects as SST. Besides, CST can also activate growth hormone secretagogue receptor 1a (GHSR1a) and the Mas-related gene X-2 receptor (MrgX2), with different biological effect from SST. CST is becoming a new cardiovascular protective endogenous peptide due to its role in the pathophysiology of the heart and blood vessels. Therefore, we reviewed the recent advances of CST in the heart and blood vessels.
In 1999, Rauca et al. found that intraventricular administration of 10.0 mmol CST significantly reduced cerebral infarct size in rats with cerebral infarction caused by middle cerebral artery occlusion when compared with saline. Further studies found that the effect of CST on cerebral ischemic injury may be mediated by SSTR2. Mastrodimou and his colleagues showed that CST could attenuate the retinal damage induced by chemical ischemia in a concentration-dependent manner. Similarly, CST also performed myocardial protection in a rat model of myocardial infarction caused by ligation of the left anterior descending artery. In the Wistar rat myocardial infarction model induced by left anterior descending ligation, CST was suggested to reduce acute myocardial infarction (AMI) area and improve cardiac function, as CST significantly increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased myocardial infarct size and serum level of cardiac troponin I (cTnI), when compared with the AMI group. Cardiomyocyte apoptosis plays an important role in myocardial infarction and the deterioration of cardiac function after myocardial infarction. Our study also found that CST significantly suppressed cardiomyocyte apoptosis in rat myocardial infarction model induced by left anterior descending ligation, as shown by a decrease in apoptotic bodies and vacuolar degeneration under electron microscopy, a decrease in the number of TUNEL-positive nuclear staining, a down-regulation of pro-apoptotic protein Bax, and an up-regulation of anti-apoptotic protein Bcl-2. Our further study found that this protective effect of CST might be related to its inhibition of endoplasmic reticulum stress, but its specific molecular regulatory mechanisms and possible receptor signaling pathways remained to be elucidated.
Sepsis is referred as a dysregulated host response to infection, which can lead to multiple organ dysfunction, accounting for more than 10% of the in-hospital mortality. The reason of septic shock involves serious infection complications related to dysregulation and high inflammation reactivity. In 2006, Gonzalez-Rey et al. found that CST could alleviate the pathological damage associated with septic shock in rodents and inhibit the expression of systemic and local inflammatory mediators, including cytokines, chemokines and acute phase proteins. Myocardial injury and dysfunction are common clinical manifestations of sepsis and septic shock, occurring in nearly 40–50% of patients. However, it is unclear what role CST plays in myocardial damage caused by septic shock. To investigate the effects of CST during sepsis, our team used a sepsis rat model induced by cecal ligation and puncture and found that CST could not only improve cardiac function and reduce cardiomyocyte apoptosis, but also significantly down-regulate the expression of glucose-regulated protein 94 (GRP94), caspase-12, and CCAAT/enhancer-binding proteins homologous protein (CHOP). Therefore, we speculate that inhibiting endoplasmic reticulum stress by CST may play an important role in protecting myocardium. We further used dithiothreitol (DDT) and lipopolysaccharide (LPS)-induced cardiomyocyte model and confirmed that CST could inhibit endoplasmic reticulum and reduce cardiomyocyte apoptosis, which can be reversed by GHSR1a receptor blockers. Since sepsis involves excessive production of inflammatory cytokines, and the NLRP3 inflammasome/interleukin 1β (IL-1β) signaling pathway plays a key role in cytokine secretion during sepsis, our team further examined whether CST reduced myocardial damage and myocardial fibrosis via NLRP3 inflammasome/caspase-1/IL-1β pathway. We observed that that CST could inhibit NLRP3 and caspase-1 activity, thereby reducing IL-1β secretion and ultimately myocardial damage. A recent clinical observation indicated CST was found to be elevated in plasma of patients with sepsis, indicating a possible marker of diagnosing sepsis. However, it still has a long way to go from the experimental and the clinical observational study of prevention and treatment of septic shock and its related myocardial injury to a tool of clinical treatment and diagnosis.
Since CST and its receptors (SSTR1-5 and GHSR1a) are widely distributed in the immune system, such as monocytes, macrophages, T lymphocytes (T cells), etc., CST is showed to play a protective role in sepsis, arthritis, inflammatory bowel disease and autoimmune encephalomyelitis, through inhibiting the secretion of inflammatory factors and chemokines, T cell proliferation and T helper cell 1 (Th1) response. CST is considered as a key factor in the bidirectional communication between neuroendocrine and immune systems, which plays a pivotal role in immune regulation. Myocarditis is an autoimmune and inflammatory cardiomyopathy caused by infection, physical and chemical factors. Myocarditis and subsequent dilated cardiomyopathy are the main causes of heart failure in young patients. Specific immune response to the myocardium is a key process of the pathogenesis of myocarditis and is mediated by self-antibodies and T-cells (mainly Th17). A mouse model of EAM induced by a fragment of cardiac myosin was used to investigate the therapeutic effect of CST on EAM. The results showed that CST could attenuate cardiac hypertrophy and myocardial injury, through inhibiting inflammatory infiltration of myocardial tissues and release of inflammatory cytokines by activating SSTRs and GHSR1a. Noteworthy, CST could significantly reduce the percentage of Th17 cells in peripheral lymphoid organs and hearts of EAM mice, without altering T-cell response (e.g., Th17-mediated responses). Therefore, we speculate that no suppression of immune response was caused by CST. These data suggest that CST may be a new treatment for autoimmune and inflammatory cardiovascular diseases, including myocarditis and dilated cardiomyopathy.
Recent evidence indicates that proliferation and migration of VSMCs contribute to the development of vascular diseases, such as atherosclerosis, restenosis and transplant vasculopathy. Inflammatory cytokines and growth factors produced excessively after injury can promote the proliferation and migration of VSMCs and the formation of neointima, and then VSMCs promote the secretion of inflammatory factors, leading to a vicious circle. Platelet-derived growth factor (PDGF) plays an essential role in this vicious cycle. Aoki et al. demonstrated that isoquinoline-type CST attenuated vascular endothelial factor-induced human umbilical vein endothelial cells (HUVECs) migration and alkaline growth factor-induced renal tubular formation, and inhibiting the proliferation of HUVECs. The effects are independent of the ERK1/2 and p38 signaling pathways. Duran-Prado et al. found that CST was highly expressed in mouse carotid arteries, human aorta, and VSMCs derived from human atherosclerotic plaques, and correlated with progression of arterial intimal hyperplasia. It was shown that CST could inhibit PDGF-induced proliferation of human aorta, which might be mediated by SST2, SST5 and GHSR1a. Further studies demonstrated that anti-proliferation and anti-migration of VSMCs caused by CST were involved in activating intracellular cyclic adenosine monophosphate (cAMP) and p38-mitogen-activated protein kinase (P38-MAPK) and inhibiting of Akt. Interestingly, CST inhibited PDGF-induced SMC migration and lamellipodia formation by inactivating Rac1 through binding to GHSR1a. These data suggest that CST participates in vascular homeostasis in paracrine and autocrine manners, providing a new treatment for vascular diseases involving neointimal formation and intimal thickening, such as arteriosclerosis and restenosis.
VC is a common pathological phenomenon in hypertension, diabetes, chronic kidney disease, and atherosclerosis, thus increasing the risk of myocardial infarction and cardiovascular events. The pathogenesis of VC involves multiple mechanisms such as inflammation, oxidative stress, imbalance of calcium and phosphorus metabolism, imbalance of pro-/anti-calcification factors, and transformation of vascular wall cells into osteoblasts. VSMCs play an indispensable role in the pathogenesis of VC.
