Original articleBenfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response
Research Highlights
► Role of pentose shunt pathway in modulation of the post-MI recovery is not known. ► Results of the present study demonstrates a novel treatment modality for chronic MI through activation of glucose-6-phosphate dehydrogenase and transketolase, the major enzymes involved in the pentose shunt pathway. ► Importantly, this study enlighten the mechanism behind poor recovery after MI in diabetic patients.
Introduction
Myocardial infarction (MI) is the leading cause of death worldwide. Patients with diabetes mellitus (DM) have less favorable outcome after MI [1], [2] or coronary artery revascularization [3], [4], and are at high risk for developing heart failure compared to non-diabetic subjects [5], [6]. Furthermore, DM is known to directly affect myocardial structure and function independently of coronary artery disease [7], [8]. These considerations underscore the urgent need of mechanistic treatments for the cure of MI, especially in the high-risk population of diabetic patients.
Recent studies have highlighted the importance of the pentose phosphate pathway for preservation of cardiomyocyte contractility in ischemia. Under conditions of increased oxidative stress, the activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of pentose phosphate pathway, is rapidly increased in cardiomyocytes with consequent neutralization of free radical injury [9]. Furthermore, translocation of G6PD to the plasma membrane of endothelial cells reportedly induces the activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS), thereby leading to promotion of angiogenesis [10], [11]. In DM, an impaired activity of G6PD and transketolase, the other pivotal enzyme that shunts glucose metabolites to the pentose pathway, results in depletion of reducing agents and accumulation of glycolysis end-products, which have deleterious effects for cardiovascular cells, such as endothelial cells, mural cells (pericytes and vascular smooth muscle cells) and cardiomyocytes [12], [13]. Of note, similar to diabetic subjects, mice with partial deficiency of G6PD demonstrate impaired angiogenesis and increased myocardial dysfunction following ischemia–reperfusion [10], [14]. However, no information exists on whether induction of G6PD-related anti-oxidative mechanism by ischemia translates in the activation of the VEGFR2/Akt signaling pathway in cardiomyocytes and whether this homeostatic response is maintained or disrupted in DM.
Benfotiamine (BFT), a vitamin B1 analogue and an activator of transketolase, reportedly ameliorates DM-induced vascular complications and healing of ischemic limbs [15], [16], [17], [18]. Furthermore, we showed that BFT prevents DM-induced diastolic dysfunction and heart failure through activation of Akt and its downstream target, proviral integration site for Moloney murine leukemia virus-1 (Pim-1) [19].
The present study investigates whether treatment with BFT protects the heart from ischemic injury and explores cellular and molecular mechanisms of cardioprotection. Results indicate that BFT significantly aids post-MI functional recovery by protecting cardiomyocytes from apoptosis through phosphorylation of VEGFR2 and Akt and activation of Pim-1. Furthermore, BFT contained the excessive activation of neurohormonal systems in the infarcted heart.
Section snippets
Ethics
Experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals (the Institute of Laboratory Animal Resources, 1996) and with approval of the British Home Office and the University of Bristol.
Experimental protocol
As summarized in Supplemental Fig. 1, 8-week old male CD1 mice (Charles River, UK) were made diabetic using streptozotocin (STZ; 40 mg/kg body weight i.p. daily for 5 days), while age- and gender-matched controls were injected with STZ-vehicle [18]. DM was confirmed by
BFT improves post-MI survival
At 14 days post-MI, only 25% of the diabetic mice in the vehicle group survived as compared to 50% of non-diabetic controls (P < 0.0001, Fig. 1). Treatment with BFT markedly improved the survival of both non-diabetic (80%) and diabetic mice (50%) as compared with the respective vehicle-treated group (P < 0.001).
BFT accelerates post-MI functional recovery
As shown in Table 1, echocardiography measurements before MI induction showed the presence of diastolic dysfunction in diabetic mice, as denoted by significantly decreased E/A ratio (P < 0.01
Discussion
Post-MI mortality and morbidity are remarkable in patients with DM [30], [31]. Different mechanisms have been proposed for the worsened recovery of diabetic infarcted hearts. Data from both diabetic patients [32] and streptozotocin-induced diabetic mice [33] suggest that a consistent loss of myocytes occurs as a consequence of oxidative stress-triggered apoptosis in the area at risk, leading to larger scars and maladaptive remodelling [34]. The present study newly shows that vitamin B1 analogue
Acknowledgments
We thank Professor Takayuki Sato, Kochi Medical School, Japan for his kind scientific advice on markers of neurohormonal activation and Mr. Paul Salvage for his kind technical assistance in immunohistochemical analyses.
Funding sources: This study was supported by a project grant from UK Diabetes Research Foundation (RD06/0003413) and Resolve (Resolve chronic inflammation and achieve healthy ageing, 202047). CE holds a British Heart Foundation (BHF) Basic Science fellowship (BS/05/01).
References (41)
- et al.
Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group
J Am Coll Cardiol
(Mar 15 1993) - et al.
The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group
J Am Coll Cardiol
(Jul 1989) - et al.
Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction
Am Heart J
(Oct 2003) - et al.
The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy
J Am Coll Cardiol
(Feb 21 2006) - et al.
Glucose-6-phosphate dehydrogenase modulates vascular endothelial growth factor-mediated angiogenesis
J Biol Chem
(Aug 22 2003) - et al.
High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells
J Biol Chem
(Dec 22 2000) - et al.
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Cell
(Oct 17 1997) - et al.
Influence of abnormal glucose metabolism on coronary microvascular function after a recent myocardial infarction
Jacc.
(Oct 2009) - et al.
Abnormal glucose metabolism in acute myocardial infarction: influence on left ventricular function and prognosis
Jacc.
(May 2009) - et al.
Oxidative damage to DNA in diabetes mellitus
Lancet
(Feb 17 1996)
Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats
Eur J Pharmacol
Glucose-6-phosphate dehydrogenase deficiency
Lancet
The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure
J Am Coll Cardiol
Neurohormonal activation in severe heart failure: relations to patient death and the effect of treatment with flosequinan
Am Heart J
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction
N Engl J Med
Impact of diabetes on five-year outcomes after vein graft interventions performed prior to the drug-eluting stent era
J Invasive Cardiol
Diabetes and coronary revascularization
Jama
Diabetic cardiomyopathy: the search for a unifying hypothesis
Circ Res
Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes
Circ Res
Glucose 6-phosphate dehydrogenase is regulated through c-Src-mediated tyrosine phosphorylation in endothelial cells
Arterioscler Thromb Vasc Biol
Cited by (61)
Synthesis, physico-chemical properties and effect of adenosine thiamine triphosphate on vitamin B<inf>1</inf> metabolism in the liver of alloxan diabetic rats
2022, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :A reason would be a shorter treatment period, 15 days in our work vs. 4–5 weeks [68,70] or 3 months [72] in the above articles. On the other hand, no improvements in blood glucose were observed in diabetic mice treated with benfotiamine (100 mg/kg for 14 days [35], 70 mg/kg for 10 wk. [36]) as well as in rats treated with thiamine (0.2% drink solution for 15 days [37]; 7 mg/kg and 70 mg/kg for 6–24 wk. [43]
Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities
2017, Genes and DiseasesCitation Excerpt :Here, we are briefly discussing the role of G6PD in metabolic stress, ROS generation, and inflammation. A balanced level of G6PD is required for the normal function of cells, whereas, increased or decreased level causes cell damages due to oxidative stress.21,56–59 As G6PD is a major enzyme that produces NADPH, it plays a crucial role in many essential metabolic pathways, such as lipid, fatty acid or cholesterol biosynthesis, and it is also involved in controlling the generation of ROS and inflammation.21,58,59
Progenitor cells from atria, ventricle and peripheral blood of the same patients exhibit functional differences associated with cardiac repair
2017, International Journal of CardiologyThiamine as a peripheral neuro-protective agent in comparison with N-acetyl cysteine in axotomized rats
2023, Iranian Journal of Basic Medical Sciences