Cardiovascular diseases (CVDs) arise from a complex interplay among genomic, proteomic, and metabolomic abnormalities. Emerging evidence has recently consolidated the presence of robust DNA damage in a variety of cardiovascular disorders. DNA damage triggers a series of cellular responses termed DNA damage response (DDR) including detection of DNA lesions, cell cycle arrest, DNA repair, cellular senescence, and apoptosis, in all organ systems including hearts and vasculature. Although transient DDR in response to temporary DNA damage can be beneficial for cardiovascular function, persistent activation of DDR promotes the onset and development of CVDs. Moreover, therapeutic interventions that target DNA damage and DDR have the potential to attenuate cardiovascular dysfunction and improve disease outcome. In this review, we will discuss molecular mechanisms of DNA damage and repair in the onset and development of CVDs, and explore how DDR in specific cardiac cell types contributes to CVDs. Moreover, we will highlight the latest advances regarding the potential therapeutic strategies targeting DNA damage signalling in CVDs.

Anwulignan is one of the monomer compounds in the lignans from Schisandra sphenanthera In this study, we observed the effect of anwulignan on intestinal ischemia/reperfusion (II/R) injury in male Sprague-Dawley rats and explored the underlying mechanisms. The results showed that pretreatment with oral anwulignan could significantly increase the mesenteric blood microcirculatory flow velocity; relieve the congestion and pathologic injury of jejunum; enhance the autonomic tension of jejunum smooth muscle and its reactivity to acetylcholine; increase the activities of superoxide dismutase, catalase, glutathione S-transferase, and choline acetyltransferase; increase the contents of acetylcholine and glutathione in the serum or jejunal tissue; decrease the activities of myeloperoxidase, protein kinase C, and nicotinamide adenine dinucleotide phosphate oxidase; reduce the contents of malondialdehyde, 8-hydroxy-2-deoxyguanosine, nicotinamide adenine, reactive oxygen species, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β; increase the expression levels of muscarinic receptor 3, PI3K, phosphorylation protein kinase B, p-GSK3β Ser9, Nrf2, p-Nrf2, heme oxygenase (decycling) 1, and b-cell lymphoma 2 in the jejunal tissue; and decrease the expression levels of p-GSK3β Tyr216, kelch-like ECH-associated protein 1, Bax, and cleaved caspase-3, suggesting that anwulignan can ameliorate II/R-induced jejunal tissue injury in rats and that the mechanism may be related to its activating the PI3K/protein kinase B pathway and then regulating the Nrf2/Anti-oxidative Response Element signaling pathway and the expression of apoptosis-related proteins to play antioxidant and antiapoptotic roles. SIGNIFICANCE STATEMENT: Anwulignan can significantly reduce jejunal tissue injury and the production of inflammatory factors in rats with intestinal ischemia-reperfusion injury, improve the antioxidant capacity, and reduce the apoptosis of jejunal tissue, and it has the effect of significantly improving intestinal ischemia-reperfusion injury in rats, suggesting that anwulignan may be used as a potential drug for the prevention and treatment of intestinal ischemia-reperfusion injury or a resource for the development of health food.

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as 'friend' or 'foe', within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease. © 2017 American Physiological Society. Compr Physiol 7:113-170, 2017.

Ischemic heart disease is the leading cause of death worldwide. An improved understanding of the mechanisms involved in myocardial injury would allow intervention downstream in the pathway where certain drugs including natural products could be efficiently applied to target the end effectors of the cell death pathway. Green tea polyphenols (GTPs) have potent anti-oxidative capabilities, which may account for their beneficial effects in preventing oxidative stress associated with ischemia injury. Although studies have provided convincing evidence to support the protective effects of GTPs in cardiovascular system, the potential end effectors that mediate cardiac protection are only beginning to be addressed. Proteomics analyses widely used to identify the protein targets for many cardiovascular diseases have advanced the discovery of the signaling mechanism for GTPs-mediated cardio-protection. This review focuses on putative triggers, mediators, and end effectors for the GTPs-mediated cardio-protection signaling pathways engaged in myocardial ischemia crisis, allowing a promising natural product to be used for ameliorating oxidative stress associated with ischemic heart diseases.

Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

Stroke is a common cause of death and serious long-term adult disability. Oxidative DNA damage is a severe consequence of oxidative stress associated with ischemic stroke. The accumulation of DNA lesions, including oxidative base modifications and strand breaks, triggers cell death in neurons and other vulnerable cell populations in the ischemic brain. DNA repair systems, particularly base excision repair, are endogenous defense mechanisms that combat oxidative DNA damage. The capacity for DNA repair may affect the susceptibility of neurons to ischemic stress and influence the pathological outcome of stroke. This article reviews the accumulated understanding of molecular pathways by which oxidative DNA damage is triggered and repaired in ischemic cells, and the potential impact of these pathways on ischemic neuronal cell death/survival. Genetic or pharmacological strategies that target the signaling molecules in DNA repair responses are promising for potential clinically effective treatment. Further understanding of mechanisms for oxidative DNA damage and its repair processes may lead to new avenues for stroke management.

The p38 mitogen-activated protein kinases (p38s) are stress-activated Ser/Thr kinases. Their activation has been associated with various pathological stressors in the heart. Activated p38 is implicated in a wide spectrum of cardiac pathologies, including hypertrophy, myocardial infarction, as well as systolic and diastolic heart failure. In this review, the specific contribution of different isoforms of p38 kinases to cardiac diseases as well as TAB-1-mediated non-canonical activation pathway are discussed as a rationale for inhibiting p38 activity to treat cardiac hypertrophy, ischemic injury, and heart failure. Finally, a summary of current clinical trials targeting p38 kinases in cardiovascular diseases is provided to highlight the potential promise as well as existing challenges of this therapeutic approach. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

There is evidence for a negative correlation between green tea consumption and cardiovascular diseases. The aim of the present study was to examine whether green tea extract (GTE) given before regional myocardial ischemia could improve depression of myocardial contractility by preventing cytosolic Ca(2+) overload. Regional ischemia-reperfusion (IR) was induced in rats by ligating the left anterior descending branch for 20 min, then releasing the ligature. Ligation induced ventricular arrhythmias in rats without GTE pretreatment, but decreased arrhythmogenesis was seen in rats pretreated 30 min earlier with GTE (400 mg/kg). During reperfusion, arrhythmias only occurred during the initial 5 min, and GTE pretreatment had no effect. After overnight recovery, serum cTnI levels were greatly increased in control post-IR rats but only slightly elevated in GTE-pretreated post-IR rats. Myocardial contractility measured by echocardiography was still depressed after 3 days in control post-IR rats, but not in GTE-pretreated post-IR rats. No myocardial ischemic injury was seen in post-IR rats with or without GTE pretreatment. Using freshly isolated single heart myocytes, GTE was found to attenuate the post-IR injury-associated cytosolic Ca(2+) overload and modulate changes in the levels and distribution of myofibril, adherens junction, and gap junction proteins. In summary, GTE pretreatment protects cardiomyocytes from IR injury by preventing cytosolic Ca(2+) overload, myofibril disruption, and alterations in adherens and gap junction protein expression and distribution.

Senescence is a general cellular process that occurs as a response to stress and damage. It forms an alternative response of cells to damage that might otherwise cause programmed cell death. Whereas telomere shortening leading to telomere dysfunction was the first described cause of senescence, it is now known that senescence can result from many sources of damage. Senescent cells are found in tissues in vivo, but the cause of senescence in these cells is mostly unknown. In many cases, senescence may be the result of the action of activated oncogenes in cells. By preventing activated oncogenes from initiating a clone of neoplastic cells, senescence acts as a protective mechanism against cancer development. Until recently, the fate of senescent cells in vivo was unknown, but new evidence indicates that they are cleared by components of the innate immune system. In this way, senescence and apoptosis act as parallel pathways by which severely damaged cells are eliminated from the body. Some senescent cells persist in tissues, in some cases increasing in frequency as a function of age. It is hypothesized that these persistent senescent cells have adverse effects on tissue function. If so, senescence may be an example of antagonistic pleiotropy, providing an anticancer mechanism in early life but having adverse effects on tissue function in late life. Much more research is needed to address the broader question of the overall impact of senescence on life span.

It is well-established that poly(ADP)ribose-polymerase (PARP) assumes major importance during ischemic brain damage, and the selective PARP-1 inhibitor PJ34 reduced spinal cord damage in murine aortic occlusion-induced ischemia/reperfusion injury. We investigated the effect of the PARP-1 inhibitor INO1001 on aortic-occlusion-related porcine spinal cord injury.

Prospective, randomized, controlled experimental study in an animal laboratory.

Ten anesthetized, mechanically ventilated, and instrumented pigs.

Animals underwent 45 min of thoracic aortic cross-clamping after receiving vehicle (n=5) or intravenous INO1001 (n=5, total dose 4 mg/kg administered both before clamping and during reperfusion). During reperfusion continuous intravenous norepinephrine was incrementally adjusted to maintain blood pressure at or above 80% of the preclamping level. Plasma INO1001 levels were analyzed by HPLC. After 4[Symbol: see text]h of reperfusion spinal cord biopsy samples were analyzed for neuronal damage (hematoxyline-eosine and Nissl staining), expression of the cyclin-dependent kinase inhibitor genes p21 and p27 (immunohistochemistry), and apoptosis (terminal deoxynucleotidyl transferase mediated nick end labeling assay).

Plasma INO1001 levels were 0.8-2.3 and 0.30-0.76 mM before and after clamping, respectively. While 3-5% of the spinal cord neurons were irreversibly damaged in the INO1001 animals, the neuronal cell injury was three times higher in the control group. Neither p21 and p27 expression nor apoptosis showed any intergroup difference.

The selective PARP-1 inhibitor INO1001 markedly reduced aortic occlusion-induced spinal cord injury. Given the close correlation reported in the literature between morphological damage and impaired spinal cord function, INO1001 may improve spinal cord recovery after thoracic aortic cross-clamping.

Oxidative stress has been implicated in the pathogenesis of chronic heart failure. The present study investigated whether the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were elevated in the serum and myocardium of patients with dilated cardiomyopathy (DCM), and furthermore whether carvedilol, a vasodilating beta-blocker with antioxidant activity, could reduce the levels.

Serum levels of 8-OHdG were measured by enzyme immunoassay in 56 patients with DCM and in 20 control subjects. DCM patients had significantly elevated serum levels of 8-OHdG compared with control subjects. Endomyocardial biopsy samples obtained from 12 DCM patients and 5 control subjects with normal cardiac function were studied immunohistochemically for the expression of 8-OHdG. Positive 8-OHdG staining was found in the nuclei of cardiomyocytes from DCM patients but not in those from control subjects. After treatment with carvedilol, the serum levels of 8-OHdG in DCM patients significantly decreased by 19%, together with amelioration of heart failure.

Levels of 8-OHdG are elevated in the serum and myocardium of patients with heart failure. Treatment with carvedilol might be effective for decreasing the oxidative DNA damage.

To detect the effect of acid fibroblast growth factor (aFGF) on P53 and P21WAF-1 expression in rat intestine after ischemia-reperfusion (I-R) injury in order to explore the protective mechanisms of aFGF.

Male rats were randomly divided into four groups, namely intestinal ischemia-reperfusion group (R), aFGF treatment group (A), intestinal ischemia group (I), and sham-operated control group (C). In group I, the animals were killed after 45 min of superior mesenteric artery (SMA) occlusion. In groups R and A, the rats sustained for 45 min of SMA occlusion and were treated with normal saline (0.15 mL) and aFGF (20 mug/kg, 0.15 mL), then sustained at various times for up to 48 h after reperfusion. In group C, SMA was separated, but without occlusion. Apoptosis in intestinal villi was determined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling technique (TUNEL). Intestinal tissue samples were taken not only for RT-PCR to detect P53 and P21WAF-1 gene expression, but also for immunohistochemical analysis to detect P53 and P21WAF-1 protein expression and distribution.

In histopathological study, ameliorated intestinal structures were observed at 2, 6, and 12 h after reperfusion in A group compared to R group. The apoptotic rates were (41.17+/-3.49)%, (42.83+/-5.23)%, and (53.33+/-6.92)% at 2, 6, and 12 h after reperfusion, respectively in A group, which were apparently lower than those in R group at their matched time points (50.67+/-6.95)%, (54.17+/-7.86)%, and (64.33+/-6.47)%, respectively, (P<0.05)). The protein contents of P53 and P21WAF-1 were both significantly decreased in A group compared to R group (P<0.05) at 2-12 h after reperfusion, while the mRNA levels of P53 and P21WAF-1 in A group were obviously lower than those in R group at 6-12 h after reperfusion (P<0.05).

P53 and P21WAF-1 protein accumulations are associated with intestinal barrier injury induced by I-R insult, while intravenous aFGF can alleviate apoptosis of rat intestinal cells by inhibiting P53 and P21WAF-1 protein expression.