Ca2+/cAMP ratio: An inflammatory index for diabetes, hypertension, and COVID-19

Abstract

Ca²⁺/cAMP ratio could serve as an inflammatory index for diseases like hyp-ertension, diabetes, and coronavirus disease 2019.

Key Words: Ca²⁺/cAMP ratio; COVID-19; Inflammatory index; Diabetes

Core Tip: Ca²⁺/cAMP ratio could serve as an inflammatory index for diseases like hypertension, diabetes, and coronavirus disease 2019.

TO THE EDITOR

There is a clear relationship between Ca²⁺ signaling, e.g., increased Ca²⁺ signals, and inflammatory responses[1,2]. Considering the cumulative data from the scientific literature, including data of high evidence such as meta-analysis and systematic reviews, we can now link Ca²⁺ dyshomeostasis as an upstream factor for hypertension, diabetes, and other inflammatory processes[1,2]. In fact, severe inflammatory outcomes are described to be linked to a critical coronavirus disease 2019 (COVID-19) result[1,3]. Intriguingly, some reports have also observed an increased severity of COVID-19 in patients with diabetes[1,3]. To assess this issue, a meta-analysis[3] was performed by conducting a literature review of Scopus, PubMed, Science Direct, and Web of Science. Observational studies, case-reports, and case-series reports that analyzed diabetes in COVID-19 patients were included in this meta-analysis[3]. The authors concluded that diabetes is a risk factor and plays a role in the disease severity and in the mortality of individuals with COVID-19. In fact, a bidirectional relationship between COVID-19 and diabetes has been established[4]. Recent data have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can produce a direct damage to the pancreas that could worsen hyperglycemia, and even cause the onset of diabetes in previously non-diabetic subjects[4]. Like diabetes, hypertension has also been recognized as a prevalent cardiovascular comorbidity in patients with COVID-19[5]. It is well established that hypertension increases the severity of SARS-CoV-2–infected patients[5]. In addition, obesity is a well-known risk factor for metabolic syndrome (MetS), hypertension, and diabetes. Recent reports revealed that it is also a vital risk factor for COVID-19, as demonstrated by a recent phenome-wide analysis of COVID-19[6].

Moreover, a link between infection with viruses and Ca²⁺ dyshomeostasis is well-discussed, e.g., altering host cellular processes in the benefit of the viruses[7-10]. Thus, Ca²⁺ dyshomeostasis induced by viruses may trigger an alteration of the host cellular system that benefits virus survival and could serve as a link for an increased severity of COVID-19 in patients with diabetes[1,3].

An interesting longitudinal study also evaluated the relationship between serum Ca²⁺ levels and the incidence of MetS, diabetes, and hypertension[11]. This study[11] was performed through cross-sectional and longitudinal analyses (period 2010–2016). Logistic regression was used for cross-sectional analysis of the association between serum Ca²⁺ levels or albumin-corrected calcium (ACCA) and the prevalence of MetS, diabetes, or hypertension. Receiver operating characteristic curve analysis was applied for calculating an optimal cut-off value of serum Ca²⁺ levels and ACCA[11]. Cox proportional regression analysis for the development of MetS, diabetes, and hypertension according to different cut-off values of serum Ca²⁺ levels and ACCA was performed. At baseline, there were 27364 participants in this study[11]. The authors[11] concluded that higher serum Ca²⁺ levels were associated with an increased risk of MetS, diabetes, and hypertension. A hypothesis which could link hypertension and higher serum Ca²⁺ levels postulates that the influx of Ca²⁺ into the smooth muscle of the arteries could lead to muscle contracture, then increasing vascular resistance and, therefore, could result in the development of hypertension[11]. Our previous reports[1,2,12-15] also discussed this issue. In fact, we postulated that dysregulation of Ca²⁺ signaling is linked to a sympathetic hyperactivity, then leading to hypertension[1,12,16]. In addition, a hypothesis which could link diabetes and higher serum Ca²⁺ levels postulates that serum Ca²⁺ is associated with insulin resistance in adipocytes and skeletal muscle[17,18]. Our previous reports are in accordance with this hypothesis[1,12,15]. In fact, whereas a physiological increase in the cytoplasmic concentration of Ca²⁺ is a significant trigger for releasing insulin, an abnormal elevation of Ca²⁺ could stimulate β-cell apoptosis, then decreasing insulin levels, contributing to diabetes[1,15].

Furthermore, reports of our group undoubtedly established that a rise of the concentration of cAMP can stimulate a Ca²⁺ release from the endoplasmic reticulum, entitled as Ca²⁺/cAMP signaling interaction[1,2,12-15]. In fact, a rise of the concentration of Ca²⁺ can markedly cause a decrease of the concentration of cAMP because of the negative feedback (Ca²⁺/cAMP signaling interaction). Thus, a disruption of this interaction can be linked with disorders, e.g., hypertension, diabetes, and COVID-19[1,2,15]. Although the interaction between these disorders may be linked with continued increases of the concentration of Ca²⁺, whether these increases could disturb Ca²⁺/cAMP signaling interaction needs more studies, e.g., in animal models and clinical trials. Indeed, previous studies corroborate this concept. For instance, in patients with diabetes, plasma concentrations of cAMP were significantly lower than those of normal subjects[19]. In addition, cAMP contents of platelets were measured and observed to be lower in hypertensive than in normotensive subjects[20]. Figure 1 summarizes previous discussion.

Figure 1 Altered Ca2⁺/cAMP ratio resulting from an inflammatory stimulus and infection with SARS-CoV-2. Altered Ca2⁺/cAMP ratio stimulates uncontrolled inflammation, leading to virus replication, increase of β-cell apoptosis and decrease of insulin levels, and sympathetic hyperactivity. Up/down arrows: Increase/decrease; COVID-19: Coronavirus disease 2019.

In conclusion, Ca²⁺/cAMP ratio could serve as an inflammatory index for diseases like hypertension, diabetes, and COVID-19[21,22].