Reactive oxygen species (ROS) are highly reactive substances generated by the chemical
utilization of oxygen inside the cells. High levels of ROS induce macromolecule damage
leading to a variety of diseases, but controlled ROS generation play a role in redox-sensitive
gene expression and cell signaling regulating physiological processes including cardiovascular
functions.
The main scope of the present special issue was to reach a broad audience of scientists
working in the field of cardiovascular redox biomedicine. We encouraged the submission
of papers approaching the topic from different points of view and at different levels,
from basic to translational research. Indeed, a collection of scientific reports and
review articles with different approaches contributed to the special issue highlighting
interesting aspects of redox biology in several cardiovascular fields. In addition,
the research topic includes an intriguing hypothesis article by Davies reporting that
adaptation of the cardiovascular system to exercise training is one of the most significant
examples of adaptive homeostasis: defined as “The transient expansion or contraction
of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling
molecules or events, or the removal or cessation of such molecules or events.” Endurance
training involves the generation of low levels of free radicals and hydrogen peroxide
which do not cause damage, but rather activate signal transduction pathways, such
as Nrf2 and NFκB, to induce mitochondrial biogenesis—the foundation of increased exercise
endurance. As with other examples of adaptive homeostasis, the effects are transient,
lasting only as long as the training is maintained. Unfortunately, the ability to
adapt to exercise training declines with age, perhaps as a result of impaired Nrf2
and NFκB signaling, as does adaptive homeostasis capacity in general.
Several original articles and reviews included in the special issue emphasize the
role of mitochondria in cardiac activity both in physiologic and pathological conditions.
The mini-review by Pagliaro et al. deals with the role of mitochondria in ischemic
and pharmacological cardiac postconditioning. The main interesting aspect of this
work is the deepening of the signaling pathways converging on mitochondria able to
preserve many of the mitochondrial functions after ischemia/reperfusion. In particular,
the role of mitochondrial components like connexin 43, mitochondrial KATP channels
and mitochondrial permeability transition pore in cardioprotective effects of postconditioning
are widely highlighted. Another review article by Penna et al. examines the role of
chaperones in the heart and the redox aspects that can influence cardiac chaperone
function, especially within mitochondria. Chaperones are stress proteins involved
in the adaptive response to stress conditions and in this review are discussed the
redox-dependent regulation of chaperones underlying the cardiac ischemia/reperfusion
injury as well as cardioprotection.
The original article by Boengler et al. point outs that depending on their amounts,
reactive oxygen species (ROS) may either be detrimental [in myocardial ischemia/reperfusion
(IR) injury] or protective (ischemic preconditioning, IPC). Here, the authors addressed
the role of the ROS-producing enzyme p66shc in IR and IPC. Following IR (not IPC),
p66shc translocated into cardiac subsarcolemmal mitochondria and this was associated
with increased ROS formation. However, p66shc-deficient hearts showed similar infarct
sizes after IR and effective cardioprotection by IPC suggesting that p66shc-derived
ROS do not contribute to IR injury per se and are not involved in the cardioprotection
by IPC. Schiattarella et al. showed that animals with mitochondrial A-kinase anchor
protein (AKAP1) knockdown or knockout are more sensitive to TAC, an experimental model
to induce pressure overload, heart hypertrophy, cardiomyocyte apoptosis and heart
failure. Indeed, animals Akap 1−/− showed increased levels of ROS, apoptotic markers
such as short caspase-3, and TUNEL positive cells in cardiac tissues. In particular,
authors discussed that aforementioned TAC-effects may be correlated with the AKT/NO
signaling, given that TAC-induced AKT signaling activation is blunted in animals knock-out
for AKAP1.
Several contributions point out the mechanisms of drugs that affect cardiovascular
system targeting redox signaling pathways. The review by Varricchi et al. deals with
cardiovascular toxicity (CTX) by chemotherapeutic agents which can alter redox homeostasis
by increasing the production of ROS and reactive nitrogen species (RNS). The article
reports that mitochondria are central targets for chemotherapeutic-induced CTX. The
authors underline that, though, the last decade has witnessed intense research related
to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental
and clinical studies are urgently needed to balance safety and efficacy of novel cancer
therapies. In this line, the paper by Riccio et al. demonstrates that the Na+ current
inhibitor, ranolazine, is able to attenuate heart dysfunction induced by trastuzumab
in animal and cellular models. The authors suggest that the cardioprotective role
of ranolazine might be due to the blunting of ROS production induced by trastuzumab,
as demonstrated in vitro. About drugs with cardioprotective effects, the work by Vieceli
Dalla Sega et al. demonstrates that ticagrelor is able to lower circulating epidermal
growth factor (EGF) which, in turn, leads to a better generation of NO in the vascular
endothelium. The authors suggest that the capacity of ticagrelor in stabilizing platelets
is also responsible for the lower release of EGF by platelets through a mechanism
mediated by P2Y12. Taken together, data here presented indicate that–in addition to
previously identified mechanisms like augmented adenosine bioavailability-the improvement
of ticagrelor of endothelial function may depend on its greater efficacy in decreasing
platelet reactivity. Interestingly, Russo et al. report a cardioprotective role for
healthy platelets mediated by sphingosine-1-phosphate-dependent pathways, in the context
of myocardial I/R. This cardioprotective effect is lost by platelets derived from
poorly controlled diabetic patients and seems inversely correlated with the redox
status and the reactivity of platelets. Antiplatelet agents might exploit the cardioprotective
potentialities of platelets. Varga et al. in their original article suggest a role
for NADPH oxidase (NOX) in ROS production during heart failure. They report that NOX4
undergoes extensive alternative splicing in human hearts, which gives rise to the
expression of different enzyme isoforms. In particular, the full-length NOX4 is significantly
upregulated in ischemic cardiomyopathy. These results may revive the development of
NOX inhibitors based on the significant novel knowledge on the modulation of NOX activity,
which may facilitate the targeting of NOXs in various diseases including myocardial
infarction. Interestingly, Nydegger et al. in their elegant research work have shown
that in the hypoxia-mediated model of pulmonary hypertension, modulation of the NO-cGMP
pathway by sildenafil contrasts pulmonary vascular and right ventricle remodeling
by an action that does not only encompass the canonical vasomodulatory effect but
involves the modulation of several biochemical pathways. The potential role of phosphodiesterase-5
for long-term treatment, and perhaps prevention, of pulmonary hypertension is suggested
and it is surely worthy of further investigation. The interesting original article
by Rocca et al. demonstrates the cardioprotective role of the G protein-coupled estrogen
receptor (GPER) expressed in the cardiovascular system, and of its selective ligand
G1 through Notch signaling pathways in female hearts. The main finding of the study
is the role of GPER in mediating the preconditioning mechanisms in normotensive and
hypertensive conditions that protect the myocardium from I/R injury. G1-induced protection
open new perspectives in the treatment of the myocardial ischemic injury. In their
original article, Andreadou et al. show that empagliflozin (EMPA), a drug approved
for type 2 diabetes management, reduces infarct size after I/R in mice and increase
cell survival and ATP levels in rat embryonic-heart-derived cardiomyoblasts (H9C2)
and endothelial cells (ECs). The protective effects of EMPA in mice are dependent
on STAT3 activation and seem associated with reduced levels of malondialdehyde, myocardial
iNOS, and interleukin-6 expression.
Recently, a great effort has been made to clarify the role of natural substances and/or
antioxidants taken with diet or as food suppliers, in the prevention or treatment
of cardiovascular diseases. On this topic, Sorriento et al. focus on antioxidants
and in particular on vitamin D as anti-hypertensive agents. Arterial hypertension
seems to depend on an imbalance between the production of ROS/RNS and the antioxidant
defense mechanisms. The association between vitamin D deficiency and hypertension
is strongly supported by literature suggesting that the supplementation of vitamin
D could really become a therapeutic strategy for hypertension if an accurate selection
of patients will be made. The authors propose that PTH levels, that regulate and are
regulated by vitamin D, could be an important discriminating parameter in the selection
of patients that could be sensitive to vitamin D supplementation. Thus, according
to authors, vitamin D represents an antioxidant that is worthwhile to further investigate.
Another compound that deserves to be studied is the melatonin. In their review article,
Jiki et al. critically discuss the cardiovascular benefits of dietary melatonin. The
authors report and discuss the papers on the effects of melatonin in different conditions,
including hypertension and I/R injury. The issue at moment is: how can we increase
the level of melatonin in human blood? Preclinical studies suggest that melatonin,
given at dietary levels, confers cardioprotection. Circulating melatonin levels may
have antioxidant capacity. However, there are many contradictory observations, still
requiring responses. The original paper by Mastantuono et al. describes the effects
of another natural antioxidant, the anthocyanin cyanidin. Studying rat pial microvascular
changes due to cerebral blood flow reduction and recovery, the authors describe the
protective mechanisms of this compound. Based on the results, they conclude that cyanidin
protects cerebral microvasculature against vascular insult. Protection is elicited
by recruiting the NO generation and a reducing ROS generation, thus preserving vascular
permeability and vasodilation. Many pathological conditions, including hyperglycemia,
may alter endothelial function through ROS/RNS overproduction. The paper by Querio
et al. shows the antioxidant properties of chamazulene, a bioactive compound present
in chamomile essential oil, in bovine aortic endothelial cells exposed to high glucose,
and hydrogen peroxide-mediated oxidative stress. Their data suggest a possible use
of this compound as a protective agent against endothelial injury.
The connection between cardiovascular system dysfunction and neurodegeneration is
highlighted by Venturelli et al. that emphasize the importance of changes in NO bioavailability,
cortical, extra-cranial, and peripheral blood flow in patients with Alzheimer's Disease
(AD). The authors believe that these are phenomena primarily associated with AD and
are not simply correlated with aging. Indeed, a relationship between AD and vascular
impairment till to the more advanced phases of AD is described. Therefore, the link
between cardiovascular and the central nervous system degenerative processes may be
the depletion of endogenous NO. Since current AD treatments targeting Aß show very
limited efficacy, potential new therapeutic approaches aimed to ameliorate the circulatory
impairment and the depletion of NO bioavailability might be of pivotal interest for
AD, and may reduce the high costs of patients' care. The study by Firinu et al. expands
this concept by showing a significant decrease in endothelial function in another
pathologic condition, namely the hereditary angioedema (HAE). In these patients, during
the symptom-free period, a strong correlation between flow-mediated dilatation and
asymmetric dimethylarginine, a strong inhibition of NO synthesis, was observed. This
is in line with the described association of HAE and early atherosclerosis.
The topic includes also other two articles that deal with central nervous system diseases,
emphasizing the cardiovascular aspects and the link with oxidative stress. In their
mini-review, Paternò and Chillon discuss the similarity between two diseases of the
CNS, ischemic stroke, and multiple sclerosis focusing especially on the astrocyte
and neuroinflammation hallmarks shared by the two pathologies. Interestingly, the
mini-review also highlight the astrocyte and neuroinflammation-targeted-strategies
for the treatment of stroke and multiple sclerosis. The paper by Messina et al. suggests
the need to broaden horizons and the study target on Autism spectrum disorders (ASD),
including oxidative stress, neurotransmitters evaluation, and sympathetic activity
measurements also related to cardiac functions. Sleep problems in ASD are a prominent
feature, considering the role of orexins (A and B) in wake-sleep circadian rhythm,
it is possible to speculate that ASD subjects may present a dysregulation in orexinergic
neurotransmission. In this context may be explained the cerebral metabolism increasing
and the autonomic hyperfunctioning in ASD sustained by high Orexin A levels.
Finally, in the special issue are included two reviews that may open new perspectives.
In their interesting review article, Deidda et al. report several studies adopting
a metabolomic approach that eventually could be helpful in elucidating mechanisms
involved in redox and nitrosative reactions in relation to cardiovascular disease.
These pieces of information may be of significant interest for both translational
values and for improving an update of the protocols on metabolomics methods in cardiovascular
diseases. By referring to teleost fish as paradigms of hypoxia- and anoxia-tolerance,
Gattuso et al. illustrate cardiac strategies that, by involving nitric oxide and its
metabolites, play a critical role in the adaptive responses to O2 limitation. Authors
emphasize the power of the teleost heart as a bioassay to decipher the intricate molecular
networks that crucially balance tissue O2 supply and demand. Information in this direction
may be of significance also in a translational perspective for human cardioprotection
and perhaps in hypoxia-mediated pulmonary hypertension.
The above-referenced articles are a clear demonstration that the research topic reached
the aim of presenting the point of view of many scientists working in the field of
redox biomedicine. The papers approached the topic from different points of view and
at different levels, from basic to translational research. We hope these articles
can contribute to the development of new ideas and advancements in the field of redox
and nitrosative signaling in the control of normal cardiovascular functions and their
disruption in diseases.
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.