Abstract
The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase‐4 (DPP‐4) levels, we investigated whether the clinically approved DPP‐4 inhibitor linagliptin reduces left ventricular stiffness in MetS‐induced cardiac disease. Sixteen‐week‐old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin‐supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F passive). The reduced F passive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP‐4 directly cleaved titin in vitro, resulting in an increased F passive, which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4‐mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS‐induced early diastolic dysfunction in human.
Highlights
The metabolic syndrome (MetS) –a cluster of hyperglyceamia, insulin resistance, obesity, hyperlipidaemia, and hypertension– is one of the most progressively escalating public health problems affecting children, adolescents, and adults worldwide
3.2 Linagliptin improves cardiac relaxation in cardiometabolic disease As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we subsequently investigated whether the clinically approved DPP176 4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease in 177 obese ZSF1 rats [4,5,6]
Isovolumic relaxation time was increased in linagliptin treated obese ZSF1 rats, this indicates that the development of diastolic dysfunction only could be partially prevented
Summary
The metabolic syndrome (MetS) –a cluster of hyperglyceamia, insulin resistance, obesity, hyperlipidaemia, and hypertension– is one of the most progressively escalating public health problems affecting children, adolescents, and adults worldwide. The MetS may cause left ventricular stiffening, an early manifestation of diastolic dysfunction [1]. Therapies to prevent the progression MetS towards left ventricular stiffening are lacking. Cardiac stiffening involves increased cardiomyocyte stiffness (Fpassive) [2], mainly due to modifications of the giant spring titin, which forms a continuous filament network in the sarcomeres of striated myocytes. Cardiac titin consists of two isoforms: the short, stiff N2B and the longer, more flexible N2BA isoform. Extension of the elastic I-band segment in both isoforms allows for passive cardiomyocyte relaxation in diastole. Cardiomyocyte stiffness and left ventricular relaxation are modulated by isoform switching and phosphorylation of titin [3]
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