Styliani Goulopoulou

Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension.

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.

Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats

AIMS Immune system activation is a common feature of hypertension pathogenesis. However, the mechanisms that initiate this activation are not well understood. Innate immune system recognition and response to danger are becoming apparent in many cardiovascular diseases. Danger signals can arise from not only pathogens, but also damage-associated molecular patterns (DAMPs). Our first hypothesis was that the DAMP, mitochondrial DNA (mtDNA), which is recognized by Toll-like receptor 9 (TLR9), is elevated in the circulation of spontaneously hypertensive rats (SHR), and that the deoxyribonuclease enzymes responsible for its degradation have decreased activity in SHR. Based on these novel SHR phenotypes, we further hypothesized that (i) treatment of SHR with an inhibitory oligodinucleotide for TLR9 (ODN2088) would lower blood pressure and that (ii) treatment of normotensive rats with a TLR9-specific CpG oligonucleotide (ODN2395) would cause endothelial dysfunction and increase blood pressure. METHODS AND RESULTS We observed that SHR have elevated circulating mtDNA and diminished deoxyribonuclease I and II activity. Additionally, treatment of SHR with ODN2088 lowered systolic blood pressure. On the other hand, treatment of normotensive rats with ODN2395 increased systolic blood pressure and rendered their arteries less sensitive to acetylcholine-induced relaxation and more sensitive to norepinephrine-induced contraction. This dysfunctional vasoreactivity was due to increased cyclooxygenase and p38 mitogen-activated protein kinase activation, increased reactive oxygen species generation, and reduced nitric oxide bioavailability. CONCLUSION Circulating mtDNA and impaired deoxyribonuclease activity may lead to the activation of the innate immune system, via TLR9, and contribute to elevated arterial pressure and vascular dysfunction in SHR.

Catecholamine response to maximal exercise in persons with Down syndrome.

Individuals with Down syndrome (DS) exhibit low peak aerobic capacities and heart rates. Although autonomic modulation is attenuated in individuals with DS at rest, the exercise response appears normal. This suggests that mechanisms other than autonomic control influence the low aerobic capacity, such as catecholamine responsiveness to exercise. The purpose of this study was to determine catecholamine responses to a peak treadmill test in a group of subjects with DS compared with a nondisabled group. Epinephrine and norepinephrine concentrations were measured at rest and immediately after graded exercise tests on a treadmill in 20 subjects with DS (mean age, 24 +/- 7 years) and 21 nondisabled subjects (mean age, 26 +/- 6 years). Catecholamines increased significantly with peak exercise in the control group (p <0.05), with little to no change in subjects with DS. In conclusion, the different catecholamine responses to peak exercise, in particular the lack of a response in individuals with the DS, may be a primary mechanism to explain the reduced peak heart rates and low work capacities observed in this population.

Mitochondrial damage-associated molecular patterns and vascular function

Immune system activation occurs not only due to foreign stimuli, but also due to endogenous molecules. As such, endogenous molecules that are released into the circulation due to cell death and/or injury alarm the immune system that something has disturbed homeostasis and a response is needed. Collectively, these molecules are known as damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs (mtDAMPs) are potent immunological activators due to the bacterial ancestry of mitochondria. Mitochondrial DAMPs are recognized by specific pattern recognition receptors of the innate immune system, some of which are expressed in the cardiovascular system. Cell death leads to release of mtDAMPs that may induce vascular changes by mechanisms that are currently not well understood. This review will focus on recently published evidence linking mtDAMPs and immune system activation to vascular dysfunction and cardiovascular disease.

Impaired vagal modulation of heart rate in individuals with Down syndrome

The attenuated heart rate (HR) and blood pressure (BP) response to exercise in individuals with Down syndrome (DS) has been attributed to autonomic dysfunction, which has been associated with obesity. Our purpose was to determine the role of autonomic control of HR to the attenuated chronotropic response observed in individuals with DS. We evaluated spectral analysis of HR variability (HRV) in 13 individuals with (BMI 32±5 kg/m2, P<0.05) and 14 without DS (BMI 26±3 kg/m2) by means of 2 min isometric handgrip at 30% of maximal force followed by recovery. Noninvasive measures of HR (ECG) and systolic BP (SBP) (Portapres) were recorded continuously. The increases in HR and SBP, and decrease in high frequency (HF) component were significantly greater in controls than in individuals with DS (P<0.05) during handgrip. The increase in LF/HF ratio was not significantly affected by handgrip and was comparable in both groups. During recovery, the decreases in HR, SBP, and LF/HF ratio, and the increase in HF were significantly greater in controls than in individuals with DS (P<0.05). Controlling for BMI did not alter these results. The attenuated HR and SBP response to the handgrip test in individuals with DS is explained by blunted vagal modulation. Our study suggests that autonomic dysfunction in individuals with DS might be independent of obesity.

Molecular mechanisms of maternal vascular dysfunction in preeclampsia

In preeclampsia, as a heterogeneous syndrome, multiple pathways have been proposed for both the causal as well as the perpetuating factors leading to maternal vascular dysfunction. Postulated mechanisms include imbalance in the bioavailability and activity of endothelium-derived contracting and relaxing factors and oxidative stress. Studies have shown that placenta-derived factors [antiangiogenic factors, microparticles (MPs), cell-free nucleic acids] are released into the maternal circulation and act on the vascular wall to modify the secretory capacity of endothelial cells and alter the responsiveness of vascular smooth muscle cells to constricting and relaxing stimuli. These molecules signal their deleterious effects on the maternal vascular wall via pathways that provide the molecular basis for novel and effective therapeutic interventions.

Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes

Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium‐derived factors, that is, relaxing factors (endothelium‐derived relaxing factors; EDRFs) and contracting factors (endothelium‐derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX‐derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4A in hypertension‐ and diabetes‐associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4A) in vascular dysfunction associated with hypertension and diabetes.

Cardiac Autonomic Control in Individuals With Down Syndrome

Our goal in this study was to compare cardiac autonomic control at rest between 50 individuals with Down syndrome and 24 control participants without disabilities. Resting autonomic function was assessed using analysis of heart rate variability. Participants with Down syndrome had reduced total heart rate variability, which indicates possible autonomic dysfunction in this population. Their VO2 peak and BMI were not significantly correlated with resting cardiac autonomic control. This may suggest that fitness level and obesity differentially affect cardiac autonomic control in persons with Down syndrome compared to their healthy, nondisabled peers.

Exercise training improves cardiovascular autonomic modulation in response to glucose ingestion in obese adults with and without type 2 diabetes mellitus

This study examined the effect of aerobic exercise training on vagal and sympathetic influences on the modulations of heart rate and systolic blood pressure in response to an oral glucose load in obese individuals with and without type 2 diabetes mellitus (T2D). Beat-to-beat arterial pressure and continuous electrocardiogram were measured after a 12-hour overnight fast and in response to glucose ingestion (75 g dextrose) in obese subjects with (T2D group, n = 23) and without (OB group, n = 36) T2D before and after 16 weeks of aerobic exercise training at moderate intensity. Autonomic modulation was assessed using spectral analysis of systolic blood pressure variability (BPV), heart rate variability (HRV), and analysis of baroreflex sensitivity (BRS). Glucose ingestion significantly increased low-frequency (LF(SBP)), low-frequency HRV (LF(RRI)), and the ratio of low- to high-frequency components of HRV (LF(RRI)/HF(RRI)), and decreased the high-frequency power (HF(RRI)) (P < .05). Exercise training increased LF(RRI) and LF(RRI)/HF(RRI) responses, and reduced HF(RRI) and LF(SBP) to glucose ingestion in both groups (P < .05), but increased fasted BRS in the OB group only (P < .05); glucose intake had no effect on BRS (P > .05). In conclusion, a 16-week exercise training program improved cardiac autonomic modulation in response to an oral glucose load in obese adults, independently of diabetes status, and in the absence of remarkable changes in body weight, body composition, fitness level, and glycemic control.

Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome

Fifty percent of trauma patients who present sepsis-like syndrome do not have bacterial infections. This condition is known as systemic inflammatory response syndrome (SIRS). A unifying factor of SIRS and sepsis is cardiovascular collapse. Trauma and severe blood loss cause the release of endogenous molecules known as damage-associated molecular patterns. Mitochondrial N-formyl peptides (F-MIT) are damage-associated molecular patterns that share similarities with bacterial N-formylated peptides and are potent immune system activators. The goal of this study was to investigate whether F-MIT trigger SIRS, including hypotension and vascular collapse via formyl peptide receptor (FPR) activation. We evaluated cardiovascular parameters in Wistar rats treated with FPR or histamine receptor antagonists and inhibitors of the nitric oxide pathway before and after F-MIT infusion. F-MIT, but not nonformylated peptides or mitochondrial DNA, induced severe hypotension via FPR activation and nitric oxide and histamine release. Moreover, F-MIT infusion induced hyperthermia, blood clotting, and increased vascular permeability. To evaluate the role of leukocytes in F-MIT-induced hypotension, neutrophil, basophil, or mast cells were depleted. Depletion of basophils, but not neutrophils or mast cells, abolished F-MIT-induced hypotension. Rats that underwent hemorrhagic shock increased plasma levels of mitochondrial formylated proteins associated with lung damage and antagonism of FPR ameliorated hemorrhagic shock-induced lung injury. Finally, F-MIT induced vasodilatation in isolated resistance arteries via FPR activation; however, F-MIT impaired endothelium-dependent relaxation in the presence of blood. These data suggest that F-MIT may be the link among trauma, SIRS, and cardiovascular collapse.