Recently, we have read with great interest the article published by Ibarrola et al. ( Clin. Sci. (Lond.) (2018) 132 , 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection is altered in the presence of LVH has yet to be determined. Pressure overload induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin 10 min before reperfusion. Rapamycin produced marked cardioprotection in normal control mice, whereas pressure overload induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocyte apoptosis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91 phox expression, superoxide production, total NO metabolites, and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91 phox assembly inhibitor gp91ds-tat or ONOO − scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarction, hindered cardiomyocyte apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects were achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic/reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardioprotection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite protects the hypertrophied heart from MI/R.

Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo , HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ 1 (transforming growth factor β 1 ) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.

H 2 S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and metabolism of H 2 S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H 2 S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.

Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline (‘norepinephrine’)] release, stimulation of α 1 -ARs (α 1 -adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5) P 3 generation and the development of arrhythmias. In the present study, we examined the effect of increased α 1A -AR drive on these responses. In hearts from non-transgenic mice (α 1A -WT), Ins(1,4,5) P 3 generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5) P 3 response was observed in hearts from transgenic mice with 66-fold overexpression of α 1A -AR (α 1A -TG). This was despite the fact that α 1A -TG hearts had 8–10-fold higher PLC responses to NE than α 1A -WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5) P 3 , PtdIns(4,5) P 2 , responded to ischaemia and reperfusion similarly in α 1A -WT and α 1A -TG mice. Thus the lack of Ins(1,4,5) P 3 generation in α 1A -TG mice is not caused by limited availability of PtdIns(4,5) P 2 . Overall, α 1 -AR-mediated PLC activity was markedly enhanced in α 1A -WT mice under reperfusion conditions, but responses in α 1A -TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5) P 3 generation after 30 min of ischaemic insult in α 1A -WT mice. However, the precursor lipid PtdIns(4,5) P 2 was also reduced by preconditioning, whereas heightened α 1A -AR activity did not influence PtdIns(4,5) P 2 responses in reperfusion. Thus preconditioning and α 1A -AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5) P 3 generation. These studies demonstrate a selective inhibitory action of heightened α 1A -AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion.

GH (growth hormone) administration during acute MI (myocardial infarction) ameliorates subsequent LV (left ventricular) dysfunction. In the present study, we examined the effects of such treatment on arrhythmogenesis. A total of 53 Wistar rats (218±17 g) were randomized into two groups receiving two intraperitoneal injections of either GH (2 international units/kg of body weight; n =26) or normal saline ( n =27), given at 24 h and 30 min respectively, prior to MI, which was generated by left coronary artery ligation. A single-lead ECG was recorded for 24 h post-MI, using an implanted telemetry system. Episodes of VT (ventricular tachyarrhythmia) and VF (ventricular fibrillation) during the first hour (phase I) and the hours following (phase II) MI were analysed. Monophasic action potential was recorded from the lateral LV epicardium at baseline and 24 h post-MI, and APD90 (action duration at 90% of repolarization) was measured. Infarct size was calculated 24 h post-MI. Infarct size and phase I VT+VF did not differ significantly between groups, but phase II hourly duration of VT+VF episodes was 82.8±116.6 s/h in the control group and 18.3±41.2 s/h in the GH group ( P =0.0027), resulting in a lower arrhythmic ( P =0.016) and total ( P =0.0018) mortality in GH-treated animals. Compared with baseline, APD90 was prolonged significantly 24 h post-MI in the control group, displaying an increased beat-to-beat variation, but remained unchanged in the GH group. We conclude that GH decreases phase II VTs during MI in the rat. This finding may have implications in cardiac repair strategies.

Therapies aimed at enhancing cardiomyocyte survival following myocardial injury are urgently required. As GHRP6 [GH (growth hormone)-releasing peptide 6] has been shown to stimulate GH secretion and has beneficial cardiovascular effects, the aim of the present study was to determine whether GHRP6 administration reduces myocardial infarct size following acute coronary occlusion in vivo . Female Cuban Creole pigs were anaesthetized, monitored and instrumented to ensure a complete sudden left circumflex artery occlusion for 1 h, followed by a 72 h reperfusion/survival period. Animals were screened clinically before surgery and assigned randomly to receive either GHRP6 (400 μg/kg of body weight) or normal saline. Hearts were processed, and the area at risk and the infarct size were determined. CK-MB (creatine kinase MB) and CRP (C-reactive protein) levels and pathological Q-wave-affected leads were analysed and compared. Evaluation of the myocardial effect of GHRP6 also included quantitative histopathology, local IGF-I (insulin-growth factor-I) expression and oxidative stress markers. GHRP6 treatment did not have any influence on mortality during surgery associated with rhythm and conductance disturbances during ischaemia. Infarct mass and thickness were reduced by 78% and 50% respectively, by GHRP6 compared with saline ( P <0.01). More than 50% of the GHRP6-treated pigs did not exhibit pathogological Q waves in any of the ECG leads. Quantitative histopathology and CK-MB and CRP serum levels confirmed the reduction in GHRP6-mediated necrosis (all P <0.05). Levels of oxidative stress markers suggested that GHRP6 prevented myocardial injury via a decrease in reactive oxygen species and by the preservation of antioxidant defence systems (all P <0.05). Myocardial IGF-I transcription was not amplified by GHRP6 treatment compared with the increase induced by the ischaemic episode in relation to expression in intact hearts ( P <0.01). In conclusion, GHRP6 exhibits antioxidant effects which may partially contribute to reduce myocardial ischaemic damage.