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Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.

ABSTRACT: Type 2 diabetes (T2D) is a multisystem disease with rapidly increasing global prevalence. Heart failure has emerged as a major complication of T2D. Dysregulated myocardial calcium handling is evident in the failing heart and this may be a key driver of cardiomyopathy in T2D, but until recently this has only been demonstrated in animal models. In this review, we describe the physiological concepts behind calcium handling within the cardiomyocyte and the application of novel imaging techniques for the quantification of myocardial calcium uptake. We take an in-depth look at the evidence for the impairment of calcium handling in T2D using pre-clinical models as well as in vivo studies, following which we discuss potential novel therapeutic approaches targeting dysregulated myocardial calcium handling in T2D.

SUBMITTER: Dattani A

PROVIDER: S-EPMC10817027 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.

Dattani Abhishek A Singh Anvesha A McCann Gerry P GP Gulsin Gaurav S GS

Journal of cardiovascular development and disease 20231230 1

Type 2 diabetes (T2D) is a multisystem disease with rapidly increasing global prevalence. Heart failure has emerged as a major complication of T2D. Dysregulated myocardial calcium handling is evident in the failing heart and this may be a key driver of cardiomyopathy in T2D, but until recently this has only been demonstrated in animal models. In this review, we describe the physiological concepts behind calcium handling within the cardiomyocyte and the application of novel imaging techniques for ...[more]

PMID: 38248882

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Project description:RATIONALE:Normal cardiac physiology requires highly regulated cytosolic Ca(2+) concentrations and abnormalities in Ca(2+) handling are associated with heart failure. The majority of approaches to identifying the components that regulate intracellular Ca(2+) dynamics rely on cells in culture, mouse models, and human samples. However, a genetically robust system for unbiased screens of mutations that affect Ca(2+) handling remains a challenge. OBJECTIVE:We sought to develop a new method to measure myocardial Ca(2+) cycling in adult Drosophila and determine whether cardiomyopathic fly hearts recapitulate aspects of diseased mammalian myocardium. METHODS AND RESULTS:Using engineered transgenic Drosophila that have cardiac-specific expression of Ca(2+)-sensing fluorescent protein, GCaMP2, we developed methods to measure parameters associated with myocardial Ca(2+) handling. The following key observations were identified: (1) Control w(1118) Drosophila hearts have readily measureable Ca(2+)-dependent fluorescent signals that are dependent on L-type Ca(2+) channels and SR Ca(2+) stores and originate from rostral and caudal pacemakers. (2) A fly mutant, held-up(2) (hdp(2)), that has a point mutation in troponin I and has a dilated cardiomyopathic phenotype demonstrates abnormalities in myocardial Ca(2+) handling that include increases in the duration of the 50% rise in intensity to peak intensity, the half-time of fluorescence decline from peak, the full duration at half-maximal intensity, and decreases in the linear slope of decay from 80% to 20% intensity decay. (3) Hearts from hdp(2) mutants had reductions in caffeine-induced Ca(2+) increases and reductions in ryanodine receptor (RyR) without changes in L-type Ca(2+) channel transcripts in comparison with w(1118). CONCLUSIONS:Our results show that the cardiac-specific expression of GCaMP2 provides a means of characterizing propagating Ca(2+) transients in adult fly hearts. Moreover, the adult fruit fly heart recapitulates several aspects of Ca(2+) regulation observed in mammalian myocardium. A mutation in Drosophila that causes an enlarged cardiac chamber and impaired contractile function is associated with abnormalities in the cytosolic Ca(2+) transient as well as changes in transcript levels of proteins associated with Ca(2+) handling. This new methodology has the potential to permit an examination of evolutionarily conserved myocardial Ca(2+)-handing mechanisms by applying the vast resources available in the fly genomics community to conduct genetic screens to identify new genes involved in generated Ca(2+) transients and arrhythmias.

Project description:Aims/hypothesisIndividuals with diabetes are at high risk of cardiovascular complications, which significantly increase morbidity/mortality. Coronary microvascular disease (CMD) is recognised as a critical contributor to the increased cardiac mortality observed in people with diabetes. Therefore, there is an urgent need for treatments that are specific to CMD. eNAMPT (extracellular nicotinamide phosphoribosyltransferase) is a damage-associated molecular pattern and TLR4 ligand, whose plasma levels are elevated in people with diabetes. This study was thus designed to investigate the pathogenic role of intracellular nicotinamide phosphoribosyltransferase (iNAMPT) and eNAMPT in promoting the development of CMD in a preclinical murine model of type 2 diabetes.MethodsAn inducible type 2 diabetic mouse model was generated by a single injection of low-dose streptozocin (75 mg/kg, i.p.) combined with a high-fat diet for 16 weeks. The in vivo effects of i/eNAMPT inhibition on cardiac endothelial cell (CEC) function were evaluated by using Nampt+/- heterozygous mice, chronic administration of eNAMPT-neutralising monoclonal antibody (mAb) or use of an NAMPT enzymatic inhibitor (FK866).ResultsAs expected, diabetic wild-type mice exhibited significantly lower coronary flow velocity reserve (CFVR), a determinant of coronary microvascular function, compared with control wild-type mice. eNAMPT plasma levels or expression in CECs were significantly greater in diabetic mice than in control mice. Furthermore, in comparison with diabetic wild-type mice, diabetic Nampt+/- heterozygous mice showed markedly improved CFVR, accompanied by increased left ventricular capillary density and augmented endothelium-dependent relaxation (EDR) in the coronary artery. NAMPT inhibition by FK866 or an eNAMPT-neutralising mAb significantly increased CFVR in diabetic mice. Furthermore, administration of the eNAMPT mAb upregulated expression of angiogenesis- and EDR-related genes in CECs from diabetic mice. Treatment with either eNAMPT or NAD+ significantly decreased CEC migration and reduced EDR in coronary arteries, partly linked to increased production of mitochondrial reactive oxygen species.Conclusions/interpretationThese data indicate that increased i/eNAMPT expression contributes to the development of diabetic coronary microvascular dysfunction, and provide compelling support for eNAMPT inhibition as a novel and effective therapeutic strategy for CMD in diabetes.

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Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.

Publications

Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.

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