Diabetic cardiovascular complications are reaching epidemic proportions and the risk of HF (heart failure) is increased 2–3-fold by diabetes mellitus. H2S (hydrogen sulfide) is emerging as a new gaseous signalling molecule in the cardiovascular system which possesses multifactorial effects on various intracellular signalling pathways. The proven cardioprotective and vasodilator activities of H2S warrant a detailed investigation into its role in diabetic cardiomyopathy. In the present issue of Clinical Science, Zhou et al. demonstrate an important therapeutic potential of the H2S pathway in diabetic cardiomyopathy.

Diabetes mellitus refers to a metabolic disorder characterized by hyperglycaemia and insufficiency of secretion or action of endogenous insulin. It has become a major health concern worldwide and its prevalence is alarming from currently 371 million to a conservative estimate of 552 million diabetics in 2030. Diabetes mellitus is predicted to be the fifth most common cause of deaths worldwide [1]. Prospective population-based studies have shown that the risk of HF (heart failure) is increased 2-3-fold by diabetes mellitus [2]. This increasing prevalence of diabetes, particularly among teenagers, reinforces concerns over the appearance of the complications of long-term diabetes during the most active and productive years of life. This global increase in diabetes mellitus is a public health crisis which requires new prevention and treatment tools. There is no effective regimen for the prevention or cure of diabetic cardiovascular complications. Clinically, blockade of the RAS with AT1R (angiotensin II type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors are beneficial in reducing the risks of diabetic cardiovascular complications [3], and discovery of the novel RAS (renin-angiotensin system) enzyme ACE2 has opened new therapeutic targets for diabetic cardiovascular complications [4,5].

In the present issue of Clinical Science, Zhou et al. [6] show that H2S (hydrogen sulfide) is also a potential therapeutic target for diabetic cardiomyopathy. H2S together with NO (nitric oxide) and CO (carbon monoxide) represents three gaseous species with important biological and pathophysiological roles. Using a STZ (streptozotocin)-induced Type 1 diabetes model in rats, Zhou et al. [6] found that daily administration of the H2S donor NaHS (sodium hydrosulfide) had anti-inflammatory, antioxidative and anti-apoptotic effects, and rescued the decline in heart function in the STZ+NaHS group. These findings by Zhou et al. [6] add to the growing body of evidence implicating a cardioprotective role of H2S in cardiovascular diseases. The biosynthesis of H2S has been attributed to three endogenous enzymes: CBS (cystathionine β-synthase), CGL (cystathionine γ-lyase) and 3-MST (3-mercaptopyruvate sulfurtransferase). In recent years, H2S has been demonstrated to have cytoprotective effects in multiple organ systems. Although high levels of H2S can be toxic, significant advances have been made regarding the physiological role of H2S in various biological systems (Figure 1). Various studies have provided scientific evidence for the cardioprotective role of the H2S in various animal models for HF, including the myocardial infarction and ischemia/reperfusion injury, and isoprenaline (isoproterenol)-induced cardiomyocyte apoptosis [7]. H2S supplementation activates the cytochrome c oxidase, increases Bcl-2 and decreases Bax and caspase 3 expression, resulting in potential anti-hypoxic and anti-apoptotic effects. Its effects on PI3K (phosphoinositide 3-kinase)/Akt pathway activation and inhibition of JNK (c-Jun N-terminal kinase) and p38-MAPK (mitogen-activated protein kinase) pathways contribute to its anti-apoptotic effects [6]. H2S possesses very potent antioxidant effects via the activation of Nrf-2 (nuclear factor-erythroid 2-related factor 2)/ARE (antioxidant-response element) signalling-induced expression of HO-1 (haem oxygenase-1) and NQO1 (NADPH:quinone oxidoreductase 1) and also inhibits ROS (reactive oxygen species)-induced ERK1/2 (extracellular-signal-regulated kinase 1/2) activation, contributing to its cardioprotective effects [6,8]. In addition, H2S also leads to vasodilation mediated through KATP channels and PDE5 (phosphodiesterase 5) inhibition [9]. Recent studies have shown a key role of H2S in the regulation of eNOS (endothelial NO synthase) activity mainly by S-sulfhydration, leading to eNOS-activation-induced NO production, and inhibition of eNOS attenuates the cardioprotective effects of H2S [10,11]. These multifactorial effects of H2S warrant an investigation of its cardioprotective effects on diabetic cardiomyopathy (Figure 1).

Mediators in H2S-induced cardioprotection

Figure 1
Mediators in H2S-induced cardioprotection

H2S is biosynthesized from homocysteine and L-cystenine in a biochemical process catalysed by CBS (cystathionine β-synthase) and CSE (cystathionine γ-lyase). H2S shows multifactorial effects on various intracellular signalling pathways, namely cytochrome c oxidase, ERK1/2 (extracellular-signal-regulated kinase 1/2), Nrf2 (nuclear erythroid 2-related factor 2)/ARE (antioxidant responsive element) signalling, apoptotic cascade and different kinase pathways, resulting in anti-hypoxic, antioxidative stress and anti-apoptotic effects. H2S also leads to vasodilation mediated by KATP channels and PDE5 inhibition, as well as S-sulfhydration of eNOS and subsequent NO production. HO-1, haem oxygenase-1; JNK, c-Jun N-terminal kinase; NQO1, NADPH: quinone oxidoreductase; PDE5, phosphodiesterase 5; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.

Figure 1
Mediators in H2S-induced cardioprotection

H2S is biosynthesized from homocysteine and L-cystenine in a biochemical process catalysed by CBS (cystathionine β-synthase) and CSE (cystathionine γ-lyase). H2S shows multifactorial effects on various intracellular signalling pathways, namely cytochrome c oxidase, ERK1/2 (extracellular-signal-regulated kinase 1/2), Nrf2 (nuclear erythroid 2-related factor 2)/ARE (antioxidant responsive element) signalling, apoptotic cascade and different kinase pathways, resulting in anti-hypoxic, antioxidative stress and anti-apoptotic effects. H2S also leads to vasodilation mediated by KATP channels and PDE5 inhibition, as well as S-sulfhydration of eNOS and subsequent NO production. HO-1, haem oxygenase-1; JNK, c-Jun N-terminal kinase; NQO1, NADPH: quinone oxidoreductase; PDE5, phosphodiesterase 5; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.

Zhou et al. [6] found decreased H2S levels in plasma and heart tissues of STZ-treated diabetic rats, and daily administration of NaHS returned the H2S levels to normal. Importantly, H2S was also decreased in the plasma of Type 2 diabetic patients compared with age matched healthy controls [12]. A previous report shows a potential role for H2S in the protection of pancreatic β-cells in high-glucose conditions [13], suggesting a possible role of H2S donor therapy in reducing β-cell loss, a key pathophysiological step in diabetes. The study by Zhou et al. [6] did not investigate the possibility that H2S may have helped to preserve the remainder of pancreatic β-cells, potentially rescuing the diabetic phenotype; however, H2S rescue of diabetic retinopathy with a similar experimental design found that blood glucose levels were not ameliorated by NaHS [14].

The in vitro work by Zhou et al. [6] is arguably also applicable to a Type 2 diabetic model because cells received insulin-containing serum. In this setting, activation of Akt signalling was attenuated by high-glucose treatment and preserved by NaHS treatment, suggesting that H2S may ameliorate the vicious cycle of high plasma glucose leading to inactivation of Akt/glucose transport signalling in Type 2 diabetes. STZ-induced diabetes in rats primarily reflect a Type 1 diabetic phenotype and therefore it is necessary for future studies to explore the role of H2S on diabetic cardiomyopathy following diet-induced models of obesity, insulin resistance and subsequent Type 2 diabetes. In addition, the genetic model of diabetes, e.g. Akita mouse model, which harbours a mutation in the insulin gene found in patient with Type 1 diabetes, is a preferable model of Type 1 diabetes.

NaHS gives a rapid burst of H2S, which has been viewed as a negative point because it is non-physiological, and several other H2S donors perhaps represent more promising therapeutic tools because they offer a slow and sustained H2S production [15]. The significant cardiac protection observed in the study by Zhou et al. [6] with once a day treatment with NaHS indicates that intermittent treatment is still effective; however, there is still likely to be significant room for dose optimization with a better understanding of the pharmacokinetics of different H2S donors. Because of the increasing incidence of global diabetes, there is a need of novel therapies for diabetes and its cardiovascular complications. Pharmacological approaches aimed at enhancing H2S action may have salutary therapeutic effects on diabetic cardiomyopathy (and the associated risk of HF) and possibly in other types of heart disease.

Abbreviations

     
  • ACE

    angiotensin-converting enzyme

  •  
  • eNOS

    endothelial NO synthase

  •  
  • HF

    heart failure

  •  
  • STZ

    streptozotocin

FUNDING

Our own work is funded by operating grants from Alberta Innovates-Health Solutions (AIHS), the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation (HSF).

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