Impact of Peroxisome Proliferator-Activated Receptor-Α On

Wang et al. Cardiovasc Diabetol (2021) 20:2 https://doi.org/10.1186/s12933-020-01188-0 Cardiovascular Diabetology REVIEW Open Access Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy Lin Wang1,2†, Yin Cai1,2,3†, Liguo Jian4, Chi Wai Cheung2, Liangqing Zhang1* and Zhengyuan Xia1,2* Abstract The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defned as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and signifcant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and infammation. There are no specifc drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofbrate, bezafbrate, clofbrate) or safe (pemafbrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium–glucose co-transporter 2 inhibitor) in treating DCM. Keywords: Diabetic cardiomyopathy, PPARα modulator, Metformin, Glucagon-like peptide 1-receptor agonists, Sodium–glucose co-transporter type 2 inhibitors Introduction reduced LV ejection fraction [1]. Although it remains Diabetic cardiomyopathy (DCM) is defned as left ven- unclear as to what initiates DCM on the molecular level, tricular (LV) dysfunction in diabetic patients without the major clinical and biochemical abnormalities in dia- coronary artery disease and hypertension [1, 2]. It is usu- betes, such as hyperglycemia, systemic insulin resist- ally asymptomatic in the early stages of its evolution [3]. ance, and impaired cardiac insulin signaling, are the risk Minimal diagnostic criteria of DCM include LV hyper- factors contributing to the pathogenesis of DCM [3, 4]. trophy, interstitial fbrosis, LV diastolic dysfunction and Emerging evidence highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes [5–7]. It has been demonstrated *Correspondence: [email protected]; [email protected]† that in obese, insulin-resistant men, abnormal LV energy 1 Department of Anesthesiology, Afliated Hospital of Guangdong metabolism is evident prior to structural and func- Medical University, Zhanjiang, China tional pathological remodeling in the heart [8]. Clinical Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Cardiovasc Diabetol (2021) 20:2 Page 2 of 15 observations by using magnetic resonance (MR) imag- on glucose, ketone body and branched chain amino acids ing and phosphorus-31-nuclear MR spectroscopy have (BCAA) (Fig. 1). In diabetic hearts, however, increased demonstrated that diastolic dysfunction and reduced fatty acid uptake and decreased glucose utilization have myocardial high-energy phosphate metabolism is evident been observed in animal models and patients [19, 20]. in asymptomatic normotensive male patients with well- Meanwhile, increased utilization of ketones as an energy controlled and uncomplicated type II diabetes (T2D) as source is also evident in the human diabetic heart [21]. compared with control subjects [9]. Tese fndings were A decrease in cardiac BCAA oxidation was observed in further demonstrated by Clarke et al. who showed that obese mouse induced by high fat diet [13] and in heart T2D patients with normal cardiac mass and function had failure patients [12]. Te switch of energy substrate pref- impaired cardiac energy metabolism [10]. Mitochon- erence in diabetic heart occurs in parallel with higher drial dysfunction can occur through several mechanisms rates of oxygen consumption and impaired oxidative involving cardiac substrate metabolic changes, impaired phosphorylation [19]. In addition, the results obtained cardiac insulin and glucose homeostasis [11–13], by using electron microscopy have demonstrated that impaired cellular and mitochondrial calcium (Ca 2+) han- mitochondria from diabetic patients are smaller with a dling [14], oxidative stress [15–17], lipotoxicity [2] and reduced capacity to retain Ca 2+ and are associated with cardiac collagen deposition [18]. reduced expression of mitochondrial fssion protein Under physiological condition, fatty acid is a major [22]. Tis suggests that changes of mitochondrial ultras- energy supplier contributing about 70% of the ATP to tructure and dynamics contribute to the development of the working heart whereas the remaining energy relies cardiomyopathy since the impairments in mitochondrial Under diabetic condition: Circulating BCAAKetones GlucoseFatty acid BCAAKetones GlucoseFatty acid Heart BCKA-CoA Acetoacetyl-CoA Pyruvate Acyl CoA ketone glucose oxidation oxidation BCAA fatty acid oxidation oxidation Acetyl-CoA Mitochondrial membrane TCA cycle NADH H+ ADP ATP H+ H+ Fig. 1 Alteration of cardiac metabolism under diabetic condition. Although circulating levels of branched chain amino acids (BCAA), ketones, glucose and fatty acids are increased under diabetic condition, their oxidation rates are not increased accordingly. Reduced BCAA and glucose oxidation, while increased ketone and fatty acid oxidation are evident in diabetic subject. Thus, reduced ATP production contributes to cardiac dysfunction Wang et al. Cardiovasc Diabetol (2021) 20:2 Page 3 of 15 function is associated with impaired cardiac contractility underlying mechanisms of DCM have come from inves- [22]. tigating rodent models. However, many of the observa- Although patients with diabetes may not all develop tions in rodent models of obesity, insulin resistance, and heart failure, clinical trials have shown that the incidence diabetes mimic what has been seen in humans with these of heart failure was increased in both male and female same pathologies. In addition, although the initial cause diabetic patients when compared with age-matched indi- of impaired glucose utilization is diferent between T1D viduals [23–27]. During the last decade, considerable and T2D diabetes, ultimately they share similar down- progress has been made in DCM management by phar- stream metabolic consequences as a result of increasing macological interventions mainly through lipid-lowering cardiomyocyte fatty acid utilization and decreased glu- therapies [28] and glycemic control strategies for the pre- cose utilization [1, 7]. Considering that T2D is by far the vention of heart failure targeted at the diabetic popula- most common type of diabetes, in this review, we focus tion [29]. Peroxisome proliferator-activated receptor α on evidence behind DCM in T2D to discuss the roles of (PPARα), a transcription factor which can present in a PPARα not only in energy metabolism but also in insulin high concentration in the heart, is involved not only in resistance, oxidative stress, infammation, and Ca2+ han- regulating lipid metabolism and glucose homeostasis dling regulation. We discuss the PPARα-related drugs in [30, 31], but also in Ca2+ handling, infammation and clinical applications. Based on the new breakthrough that oxidative stress in heart [32]. Mice with cardiac specifc some anti-diabetic drugs are associated with a lower risk PPARα over-expression exhibited a similar phenotype of heart failure

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