**1. Introduction**

Patients with diabetes mellitus have an increased cardiovascular mortality rate and, in particular, cardiovascular complications are the leading cause of diabetes-related morbidity and mortality. Diabetes mellitus is a well-recognized risk factor for developing heart failure and it also can affect cardiac structure and function even in the absence of traditional cardio‐ vascular risk factors. Four decades ago Rubler and colleagues introduced the term 'diabetic cardiomyopathy' describing diabetic patients with congestive heart failure and normal coronary arteries [1]. Since then, many epidemiological and clinical studies have documented the existence of this entity in humans [2].

Individuals with diabetes mellitus (DM), both type 1 DM as well as type 2 DM, have an increased risk of developing end-organ damage. Clinically, the concept of diabetic cardiomy‐ opathy is defined as ventricular dysfunction that occurs independently of coronary artery disease and hypertension, *i.e.* as a distinct primary disease process which develops secondary to a metabolic insult and results in structural and functional abnormalities of the myocardium leading to heart failure. Diabetic cardiomyopathy in humans is predominantly manifested by diastolic dysfunction, which may precede the development of systolic dysfunction [3]. Interestingly, only approximately 30% of type 2 DM and type 1 DM patients develop diabetic nephropathy, in contrast to diabetic cardiomyopathy that is present in 50% type 2 DM patients and diabetic retinopathy diagnosed in more than 90% of type 1 DM patients [4; 5]. This indicates a different time-course of end-organ damage in DM. Consequently, individual cell types are differentially sensitive to high blood glucose-induced damage likely because of different expression or activity of molecular factors responsible for damage activation and progression.

© 2013 Klimas; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The prevalence of heart failure (HF) in the general population ranges from 1 to 4%, but in diabetic patients it is 12%, rising to 22% in those over the age of 64 years [6; 7]. The Framingham Heart Study reported a 2.4-fold increase in the incidence of HF in diabetic men and a 5.1-fold increase in diabetic women, when compared with age-matched controls [8; 9]. Diabetic patients are also more likely than non-diabetic patients to develop HF following myocardial infarction, despite comparable infarct sizes [10].

a role not only in beginning but also in development of diabetic cardiomyopathy. These are (1) hepatocyte growth factor/c-Met signalling cascade, and (2) calcium release system.

Potential Target Molecules in Diabetic Cardiomyopathy: Hepatocyte Growth Factor (HGF) and…

http://dx.doi.org/10.5772/55780

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The hepatocyte growth factor (HGF) is known to be involved in a huge variety of cellular processes playing a major role in the repair and regeneration of various tissues, including the liver, kidney, lung, and stomach. In addition, it is involved in embryogenesis, organ develop‐ ment and also carcinogenesis, and its role in autoimmune diseases has been suggested as well

Liver regeneration has long been a subject of active research, because it has impressive regenerative capacities. Humoral factors that trigger liver cell growth, and so hepatic regen‐ eration, have been detected in the blood circulation of liver-injured animals, and many researchers have tried to isolate these factors ensuring this liver characteristic. One of them, HGF was first recognised as a molecule that stimulates hepatocyte proliferation and so to be a key player in the regulation of liver regeneration. It was originally identified in the plasma of partially hepatectomised rats and initially thought to be a liver-specific mitogen [20; 21; 22]. Actually, HGF is known to be a multifunctional cytokine and such as it has been a subject

Physiologically, HGF is a mesenchyme-derived pleiotropic growth factor which consists of two polypeptide chains, heavy 69-kDa alpha-chain and a light 34-kDa beta-chain which are held together by a disulfide bond. Like plasminogen, HGF is synthesised as pro-HGF, an 82 kDa single-chain inactive precursor, and subsequently transformed in the active heterodimer [24]. HGF is latent in normal states, and is activated specifically at the site of tissue injury, predominantly by HGF activator - HGFA [19; 25; 26]. The domains of HGF are very similar to those of proteases in the blood coagulation and fibrinolytic system, HGF shows the highest similarity to plasminogen (about 40% amino acid similarity). Thus, the HGF system is

The HGF receptor c-Met is a transmembrane tyrosine kinase that mediates several biological responses after stimulation by its cognate ligand. c-Met is synthesised as a precursor (170 kDa) and then, it is converted into the active disulphide-linked heterodimer composed of a 50 kDa extracellular alpha-chain and a longer 145 kDa beta-chain with a transmembrane helix and a cytoplasmic portion. The alpha-chain is exposed extracellularly, while the beta-chain is a transmembrane subunit containing an intracellular tyrosine kinase domain [27; 28; 29; 30]. Multiple biological effects of HGF/c-Met system on a wide variety of cells have been docu‐ mented. HGF is a cytokine regulating cell growth, cell motility and morphogenesis of various types of cells. Additionally, mitogenic, motogenic, chemotactic and anti-apoptotic activities of HGF have been documented on multiple cell type. This cytokine stimulates endothelial proliferation and, consequently, angiogenesis, as well as stimulates growth of other target cells

**2. Hepatocyte growth factor/c-Met signalling**

of immense research efforts during the past decade [23].

functionally linked to the blood coagulation and fibrinolytic system.

**2.1. Structure and function of HGF and c-Met**

[18; 19].

Based on the assumption of detrimental effects of hyperglycaemia on various tissues, reduction of blood glucose would reverse (or at least reduce) the development of end-organ damage. However, recent data showed unexpected findings. Castagno and colleagues conducted a meta-analysis of randomized controlled trials comparing strategies of more versus less intensive glucose-lowering that reported HF events. Interestingly, it became evident that tight glycemic control in patients with type 2 DM did not reduce the risk of HF and, additionally, when glucose lowering was achieved with thiazolidinediones, it increased that risk [11]. Additionally, evidence for a direct, causal link between insulin resistance, a hallmark of diabetes, and ventricular dysfunction has not been established [12]. The reason why intensive glucose control does not lead to the reduction in risk of HF predicted by epidemiological studies is uncertain but it may reflect an insufficient duration of treatment or follow-up, a treatment intervention too late in the course of the disease, off-target toxicity of the treatments used, or the possibility that hyperglycemia *per se* does not directly govern the development of HF in diabetic patients. In other words, hyperglycaemia could be a trigger of molecular changes causing end-organ damage, which are later regulated at least partially independently from the systemic glucose changes. These assumptions foster the search for local signalling molecules involved in end-organ damage in DM.

It is widely accepted that the pathogenesis of diabetic cardiomyopathy is multifactorial. Beyond the stereotypical function of metabolism as a provider of ATP, alterations in metabolic flux within the cell create essential signals for the adaptation of the heart to disturbed blood sugar regulation and insulin abnormalities in DM. In general, the prevailing concept of the heart's response to changes in its environment is a complex network of interconnecting signal transduction cascades where the focus is on communication of various cell surface receptors, heterotrimeric G-proteins, protein kinases, and transcription factors [13]. Several hypotheses have been proposed, including autonomic dysfunction, metabolic derangements, abnormali‐ ties in ion homeostasis, alteration in structural proteins, and interstitial fibrosis, and increased glycation of interstitial proteins such as collagen, which results in myocardial stiffness and impaired contractility [2]. Collectively, metabolic imbalance induces alterations in down‐ stream transcription factors which result in changes in gene expression, myocardial substrate utilization, myocyte growth, endothelial function and myocardial compliance [14]. Indeed, alterations in gene expression have been observed for a number of key inducer or transducer molecules in diabetic cardiomyopathy. In particular, oxidative stress due to increased pro‐ duction of reactive oxygen species (ROS) by multiple sources, such as the NADPH oxidase or dysfunctional nitric oxide (NO)-signaling cascade, is considered to be a principal mechanism involved in the development of diabetic cardiomyopathy [15; 16; 17]. However, this review focuses on two of them which are currently not in the centre of interest but which might play a role not only in beginning but also in development of diabetic cardiomyopathy. These are (1) hepatocyte growth factor/c-Met signalling cascade, and (2) calcium release system.
