The Potential Role of Undercarboxylated Osteocalcin Upregulation in Microvascular Insufficiency in a Rat Model of Diabetic Cardiomyopathy

Abstract

Background: Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology. Materials and Methods: Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies. Results: Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns. Conclusion: Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.

Circulating Undercarboxylated Osteocalcin as Estimator of Cardiovascular and Type 2 Diabetes Risk in Metabolic Syndrome Patients

“…These findings strengthen our above-mentioned results, suggesting that serum levels of ucOC could be a potential biomarker to estimate cardiovascular and T2D risk in MetS patients. In addition, based on the aforementioned evidences, in the future, ucOC might become a therapeutic target to prevent cardiovascular events as reported by recent studies conducted in animal models 52,53 .…”

Role of circulating molecules in age-related cardiovascular and metabolic disorders

“…Some studies showed ucOC was a main bioactivity form of OC, contributing to the regulation in glucose homeostasis and energy metabolism [ 99 , 100 ]. Another study showed ucOC improved microvascular insufficiency and myocardial dysfunction in a rat diabetic cardiomyopathy model [ 101 ]. However, the following studies have challenged these findings by showing no endocrine abnormalities in OC-deficient mice [ 102 , 103 ].…”

Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology

“…Unlike ucOC metabolic functions, OC mechanistic insights in cardiovascular health are fewer and equivocal. Several animal studies have suggested that ucOC may protect vasculature under T2D conditions ( Figure 1 ) [ 14 , 57 , 58 ]. For instance, ucOC administration improved diastolic blood pressure, endothelium-dependent relaxation, and aortic atherosclerotic plaque formation in high-fat diet (HFD)-fed apolipoprotein E (ApoE) −/− mice [ 14 ].…”

“…For instance, ucOC administration improved diastolic blood pressure, endothelium-dependent relaxation, and aortic atherosclerotic plaque formation in high-fat diet (HFD)-fed apolipoprotein E (ApoE) −/− mice [ 14 ]. In diabetic rats, the enhancement of circulatory ucOC, either by ucOC or warfarin administration, improved arterial stiffness, vascularization, capillary density, and neovascularization and decreased myocardial fibrosis [ 57 , 58 ]. However, whether these improvements are from ucOC acting directly on vascular cells or are as a consequence of improved metabolic outcomes remains unknown.…”