The potential effects of DPP‐4 inhibitors on cardiovascular system in COVID‐19 patients

Abstract With the outbreak of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the public healthcare systems are facing great challenges. Coronavirus disease 2019 (COVID‐19) could develop into severe pneumonia, acute respiratory distress syndrome and multi‐organ failure. Remarkably, in addition to the respiratory symptoms, some COVID‐19 patients also suffer from cardiovascular injuries. Dipeptidyl peptidase‐4 (DPP‐4) is a ubiquitous glycoprotein which could act both as a cell membrane‐bound protein and a soluble enzymatic protein after cleavage and release into the circulation. Despite angiotensin‐converting enzyme 2 (ACE2), the recently recognized receptor of SARS‐CoV and SARS‐CoV‐2, which facilitated their entries into the host, DPP‐4 has been identified as the receptor of middle east respiratory syndrome coronavirus (MERS‐CoV). In the current review, we discussed the potential roles of DPP‐4 in COVID‐19 and the possible effects of DPP‐4 inhibitors on cardiovascular system in patients with COVID‐19.

similar outer membrane spike glycoproteins among the coronavirus, it is possible that DPP-4 might also be a functional receptor of SARS-CoV-2. Like angiotensin-converting enzyme 2 (ACE2), DPP-4 played important roles in cardiovascular physiological processes and metabolism homeostasis. Here, we review the potential roles of DPP-4 in COVID-19, especially in the cardiovascular injury of COVID-19 patients.

| H UMAN DPP-4 MI G HT B E A SAR S -CoV-RECEP TOR
DPP-4 could present as a membrane binding protein or a cleaved soluble enzyme protein. It has been reported that membrane-associated human DPP-4, as a functional MERS-CoV receptor, interacted with MERS-CoV through the spike glycoprotein S1b domain to facilitate the entry of MERS-CoV. 3 Moreover, blocking spike protein S1 or the receptor-binding domain (RBD) of the MERS-CoV Spike protein could directly against MERS-CoV binding to human DPP-4, thereby prevent MERS-CoV infection. 5 Considering the similarity among MERS-CoV and the other coronavirus, it has been speculated that membrane-associated human DPP-4 might also be a functional SARS-CoV-2 receptor. 6 Moreover, Naveen et al detected that the S1 domain of SARS-CoV-2 spike glycoprotein, the key immunoregulatory factor for hijacking and virulence, potentially interacted with the human DPP-4 by overall homo-trimer model structure. 7 However, whether DPP-4 is indeed a direct receptor of SARS-CoV-2 remains to be further verified.

| THE ROLE OF DPP-4 IN C ARD I OVA SCUL AR INJ URY
One of the major functions of DPP-4 is degrading incretin hormones, including incretin hormones (glucagon-like peptide-1 [GLP-1] and gastric inhibitory polypeptide [GIP]), cytokines, chemokines, neuropeptides and growth factors. 8 It is well-known that GLP-1 and GIP promote insulin secretion from the pancreatic β cells and suppress glucagon secretion from other cells. Therefore, the inhibitors of DPP-4 are widely used to treat diabetes. Moreover, further studies find that DPP-4 is also involved in the cardiovascular complications of diabetes.
In atherosclerosis, the key pathogenesis is chronic inflammation characterized by accumulation of plaques within the arteries. 9 It was discovered that DPP-4 enhanced monocytes migration to atherosclerotic plaque and down-regulated the expression of adiponectin, which promoted inflammation and the formation of atherosclerotic plaques. 10 Moreover, DPP-4 could down-regulate stromal-derived factor 1 (SDF-1), a chemoattractant for multiple cell types, 11 while inhibition of SDF-1-mediated chemical protection and proliferation of hematopoietic stem cells and progenitor cells would inhibit neovascularization and the recovery of tissue damage. 12 In vein endothelial cells, by inhibiting the GLP-1R signalling pathway, DPP-4 could also promote the development of atherosclerosis. 13 In addition to atherosclerosis, DPP-4 also plays a negative role in the process of heart failure. DPP-4 could degrade brain natriuretic peptide (BNP), which is secreted from the cardiac ventricles in response to stretch, 14 into a less potent metabolite BNP (3-32), resulting in a loss of the BNP-mediated protective effects on the heart. Moreover, DPP-4 could also inhibit the activation of GLP-1R, which localized in the cardiac atria, reduce the secretion of atrial natriuretic peptide and increase the blood pressure. 15 Thus, DPP-4 inhibitor therapy may have additional favourable influences on cardiovascular system.

| THE P OTENTIAL EFFEC TS OF DPP-ON C ARD I OVA SCUL AR SYS TEM IN COV I D -19
As mentioned above, DPP-4 might be the functional SARS-CoV-2 receptor which facilitates the entry of SARS-CoV-2 into the host cells, including cardiomyocytes. Although the presence of SARS-CoV-2 in the heart was confirmed by biopsy, as well as myocarditis was observed in certain COVID-19 patients, the underlying mechanism of SARS-CoV-2-induced cardiac injury still needs further investigation.
SARS-CoV-2 might damage the cardiomyocytes directly, and the cardiomyocytes might be injured indirectly via the systemic cytokine storm or the interactions between organs.
Evidence from severely ill patients with COVID-19 suggested that the release of cytokines and chemokines was delayed in respiratory epithelial cells, dendritic cells (DCs) and macrophages at the early stage of SARS-CoV-2 infection. 16 Later, it was found that high levels of pro-inflammatory cytokines (IL-6, IL-10 and TNF-α), lymphopenia (reduced CD4 + and CD8 + T cells) and low levels of antiviral factors (interferon, IFNs) were positively associated with the severity of COVID-19. 17 Similar findings were also observed in SARS-CoV and MERS-CoV infected human airway epithelial cells, THP-1 cells, human peripheral blood monocyte-derived macrophages and DCs. 18 Although inflammation initially only damages limited organs, such as the lungs, an over-activated inflammatory response will spread all over the body rapidly, including the heart. This maybe one of the rea-

| THE FUN C TI ON OF DPP-4 INHIB ITOR S IN COVID -19
Early control of cytokine storms through immunomodulators, cy-

| CON CLUS ION
In this review, we put forward a hypothesis that DPP-4 might participate in the process of SARS-CoV-2 infection. This may promote COVID-19 progression towards an hyperinflammatory state, which could damage the cardiovascular system. Meanwhile, DPP-4 inhibitors could inhibit the over-activated inflammatory caused by SARS-CoV-2 and thus improve cardiovascular function. Moreover, more clinical and laboratory evidence about the effects of DPP-4 inhibitors on COVID is urgently needed.

ACK N OWLED G EM ENTS
We thank all our colleagues from the Division of Cardiology, Tongji Hospital, as well as all the medical staff fighting against COVID-19, for their tremendous efforts.