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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 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.

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This study examined the effects of aerobic exercise without weight loss, a hypocaloric high monounsaturated fat diet, and diet plus exercise (D+E) on total abdominal and visceral fat loss in obese postmenopausal women with type 2 diabetes. Thirty-three postmenopausal women (body mass index, 34.6 +/- 1.9 kg/m(2)) were assigned to one of three interventions: a hypocaloric high monounsaturated fat diet alone, exercise alone (EX), and D+E for 14 wk. Aerobic capacity, body composition, abdominal fat distribution (magnetic resonance imaging), glucose tolerance, and insulin sensitivity were measured pre- and postintervention. Body weight ( approximately 4.5 kg) and percent body fat ( approximately 5%) were decreased (P < 0.05) with the D and D+E intervention, whereas only percent body fat ( approximately 2.3%) decreased with EX. Total abdominal fat and sc adipose tissue (SAT) were reduced with the D and D+E interventions (P < 0.05), whereas visceral adipose tissue (VAT) decreased with the D+E and EX intervention, but not with the D intervention. EX resulted in a reduction in total abdominal fat, VAT, and SAT (P < 0.05) despite the lack of weight loss. The reductions in total abdominal fat and SAT explained 32.7% and 9.7%, respectively, of the variability in the changes in fasting glucose levels, whereas the reductions in VAT explained 15.9% of the changes in fasting insulin levels (P < 0.05). In conclusion, modest weight loss, through either D or D+E, resulted in similar improvements in total abdominal fat, SAT, and glycemic status in postmenopausal women with type 2 diabetes; however, the addition of exercise to diet is necessary for VAT loss. These data demonstrate the importance of exercise in the treatment of women with type 2 diabetes.

Emerging evidence suggests that in addition of being the “power houses” of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mitochondrial DNA (mtDNA) that acts via Toll-like receptor 9 (TLR9), a pattern recognition receptor of the immune system, which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion with bacterial DNA stems from evolutionary conserved similarities between bacteria and mitochondria. Mitochondrial DNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. Preeclampsia (PE) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The etiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulate TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and intrauterine growth restriction. The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE and anti-TLR9 treatments may be promising in the management of the disease.

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. Abbreviations AA, arachidonic acid; AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK, AMP-activated protein kinase; CDK2, cyclin-dependent kinase 2; cPLA2, cytosolic PLA2; DOCA, deoxycorticosterone-acetate; E2, 17β-oestradiol; ECs, endothelial cells; EDCF, endothelium-derived contracting factor; EDHF, endothelium-derived hyperpolarizing factor; EDRF, endothelium-derived relaxing factor; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; ET-1, endothelin-1; GK, Goto-Kakizaki; GPER, G protein-coupled oestrogen receptor; HETEs, hydroxyeicosatetraenoic acid; HO-1, haem oxygenase-1; HUVEC, human umbilical vein endothelial cells; L-NAME, N G -nitro-l-arginine methyl ester; L-PGDS, lipocalin-type PGD synthase; MLC20, myosin light chain 20; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; OLETF, Otsuka Long-Evans Tokushima Fatty; OPN, osteopontin; PDGFR, platelet-derived growth factor receptor; PGI2, prostacyclin; PGIS, prostacyclin synthase; ROCK, Rho kinase; ROS, reactive oxygen species; S6K, S6 kinase; SHR, spontaneously hypertensive rats; SMCs, smooth muscle cells; STZ, streptozotocin; TP, TxA2/endoperoxide receptor; TxA2, thromboxane A2; TxS, thromboxane synthase; Up4A, uridine adenosine tetraphosphate; VP, vasopressin; WKY, Wistar-Kyoto ratsThe endothelium plays a pivotal role in the regulation of vascular tone (Vapaatalo and Mervaala, 2001;Pries and Kuebler, 2006;Flammer and Luscher, 2010;Toda et al., 2010;Flammer et al., 2012; Favero et al., 2014). In response to mechanical forces (e.g. shear stress) and endogenous ligands, endothelial cells (ECs) release a diversity of factors that mediate or directly induce vascular smooth muscle contraction or relaxation (Vapaatalo and Me...

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.