Scavenger receptor A (SR-A), also known as the macrophage scavenger receptor and cluster of differentiation 204 (CD204), plays roles in lipid metabolism, atherogenesis, and a number of metabolic processes. However, recent evidence points to important roles for SR-A in infammation, innate immunity, host defense, sepsis, and ischemic injury. Herein, we review the role of SR-A in infammation, innate immunity, host defense, sepsis, cardiac and cerebral ischemic injury, Alzheimer's disease, virus recognition and uptake, bone metabolism, and pulmonary injury. Interestingly, SR-A is reported to be host protective in some disease states, but there is also compelling evidence that SR-A plays a role in the pathophysiology of other diseases. These observations of both harmful and beneficial effects of SR-A are discussed here in the framework of inflammation, innate immunity, and endoplasmic reticulum stress.

Spinal cord stimulation (SCS) inhibits substance P (SP) release and decreases the expression of the transient receptor potential vanilloid 1 (TRPV1) in the spinal cord at thoracic 4 (T4) during cardiac ischemia in rat models (. Ding et al., 2007). We hypothesized that activation of TRPV1 in the T4 spinal cord segment by intermittent occlusion of the left anterior descending coronary artery (CoAO) mediates spinal cord SP release. Experiments were conducted in urethane-anesthetized Sprague-Dawley male rats using SP antibody-coated microprobes to measure SP release at the central terminal endings of cardiac ischemic-sensitive afferent neurons (CISAN) in the spinal T4 dorsal horns. Vehicle, capsaicin (CAP; TRPV1 agonist) and capsazepine (CZP; TRPV1 antagonist) were injected into the left T4 prior to stimulation of CISAN by intermittent CoAO (with or without upper cervical SCS). CAP induced endogenous SP release from laminae I and II in the T4 spinal cord above baseline. Conversely, CZP injections significantly inhibited SP release from laminae I-VII in the T4 spinal cord segment below baseline. CZP also attenuated CoAO-induced SP release, while T4 injections of CZP with SCS completely restored SP release to basal levels during CoAO activation. CAP increased the number of c-Fos (a marker for CISAN activation) positive T4 dorsal horn neurons compared to sham-operated animals, while CZP (alone or during CoAO and SCS. +. CoAO) significantly reduced the number of c-Fos positive neurons. These results suggest that spinal release of the putative nociceptive transmitter SP occurs, at least in part, via a TRPV1 mechanism.

The beneficial effects of angiotensin II type 1 (AT1) receptor blockers (ARB) in cerebrovascular disease have been shown in clinical trials. However, the effects of ARBs vary based on their unique pharmacologic properties. In this study, we focused on telmisartan, a fat-soluble ARB with selective peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity, and investigated its effects on ischemic injury in cerebral vasculature using murine models of both transient and permanent focal ischemia. Analysis by triphenyltetrazolium-staining revealed that pre-treatment of mice with telmisartan reduced stroke volume 72 h after the transient ischemic insult in a dose-dependent manner, though such treatment did not reduce stroke volume due to permanent ischemia. Transient ischemia induced pro-inflammatory adhesion molecules, such as ICAM-1 and P-selectin in the ischemic region, and treatment with telmisartan diminished the expression of these adhesion molecules with diminished infiltration of inflammatory cells. The beneficial effect of telmisartan was attenuated, in part, by administration of a PPARγ antagonist. Treatment with valsartan (an ARB without PPARγ agonist activity) also decreased ischemic injury after transient ischemia, though to a lesser extent than telmisartan. Our findings indicate that telmisartan has a beneficial effect in a murine model of ischemia/reperfusion injury through blockade of AT1 receptors, and, in addition, due to a positive effect via its specific anti-inflammatory PPARγ agonist activity.

The innate immune response is involved in the pathophysiology of cerebral ischemia-reperfusion (I/R) injury. Recent evidence suggests that scavenger receptors have a role in the induction of innate immunity. In this study, we examined the role of scavenger receptor A (SR-A) in focal cerebral I/R injury. Both SR-A-/- mice (n=10) and age-matched wild-type (WT) mice (n=9) were subjected to focal cerebral ischemia (60 minutes), followed by reperfusion (for 24 hours). Infarct size was determined by TTC (triphenyltetrazolium chloride) staining. The morphology of neurons in the brain sections was examined by Nissl's staining. Activation of intracellular signaling was analyzed by western blot. Cerebral infarct size in SR-A -/- mice was significantly reduced by 63.9% compared with WT mice after cerebral I/R. In SR-A -/- mice, there was less neuronal damage in the hippocampus compared with WT mice. Levels of FasL, Fas, FADD, caspase-3 activity, and terminal deoynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling-positive apoptotic cells were significantly increased in WT mice after cerebral I/R, but not in SR-A -/- mice. Cerebral I/R increased nuclear factor-B activation in WT mice, but not in SR-A -/- mice. These data suggest that SR-A has a central role in cerebral I/R injury and that suppression of SR-A may be a useful approach for ameliorating brain injury in stroke patients.

Objective: The mechanisms by which lipopolysaccharide (LPS) pretreatment induces cardioprotection following ischaemia/reperfusion (I/R) have not been fully elucidated. We hypothesized that activation of phosphoinositide 3-kinase (PI3K)/Akt and high mobility group box 1 (HMGBx1) signaling plays an important role in LPS-induced cardioprotection. Methods: In in vivo experiments, age- and weight-matched male C57BL/10Sc wild type mice were pretreated with LPS before ligation of the left anterior descending coronary followed by reperfusion. Infarction size was examined by triphenyltetrazolium chloride (TTC) staining. Akt, phospho-Akt, and HMGBx1 were assessed by immunoblotting with appropriate primary antibodies. In situ cardiac myocyte apoptosis was examined by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. In an in vitro study, rat cardiac myoblasts (H9c2) were subdivided into two groups, and only one was pretreated with LPS. After pretreatment, the cells were transferred into a hypoxic chamber under 0.5% O2. Levels of HMGBx1 were assessed by immunoblot. Results: In the in vivo experiment, pretreatment with LPS reduced the at risk infarct size by 70.6% and the left ventricle infarct size by 64.93% respectively. Pretreatment with LPS also reduced cardiac myocytes apoptosis by 39.1% after ischemia and reperfusion. The mechanisms of LPS induced cardioprotection involved increasing PI3K/Akt activity and decreasing expression of HMGBx1. In the in vitro study, pretreatment with LPS reduced the level of HMGBx1 in H9c2 cell cytoplasm following hypoxia. Conclusion: The results suggest that the cardioprotection following I/R induced by LPS pretreatment involves PI3K/Akt and HMGBx1 pathways.

Populations of intrathoracic extracardiac neurons transduce myocardial ischemia, thereby contributing to sympathetic control of regional cardiac indices during such pathology. Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) modulates such local reflex control. In 10 anesthetized canines, middle cervical ganglion neurons were identified that transduce the ventricular milieu. Their capacity to transduce a global (rapid ventricular pacing) vs. regional (transient regional ischemia) ventricular stress was tested before and during SCS (50 Hz, 0.2 ms duration at 90% MT) applied to the dorsal aspect of the T1 to T4 spinal cord. Rapid ventricular pacing and transient myocardial ischemia both activated cardiac-related middle cervical ganglion neurons. SCS obtunded their capacity to reflexly respond to the regional ventricular ischemia, but not rapid ventricular pacing. In conclusion, spinal cord inputs to the intrathoracic extracardiac nervous system obtund the latter's capacity to transduce regional ventricular ischemia, but not global cardiac stress. Given the substantial body of literature indicating the adverse consequences of excessive adrenergic neuronal excitation on cardiac function, these data delineate the intrathoracic extracardiac nervous system as a potential target for neuromodulation therapy in minimizing such effects.

The brain's resistance to ischemic injury can be transiently augmented by prior exposure to a sub-lethal stress stimulus, i.e. preconditioning. It has been reported that Toll-like receptors (TLRs) are involved in the preconditioning-induced protective effect against ischemic brain injury. In this study, we investigated the effect of preconditioning with a TLR2 specific ligand, Pam3CSK4, on focal cerebral ischemia/reperfusion (I/R) injury in mice. Pam3CSK4 was administered systemically 24 h before the mice were subjected to focal cerebral ischemia (1 h) followed by reperfusion. Cerebral infarct size was determined, blood brain barrier (BBB) permeability was evaluated, and expression of tight-junction proteins were examined after focal cerebral I/R. Results showed that pre-treatment with Pam3CSK significantly reduced brain infarct size (1.9 ± 0.5% vs 9.4 ± 2.2%) compared with the untreated I/R group. Pam3CSK4 pre-treatment also significantly reduced acute mortality (4.3% vs 24.2%), preserved neurological function (8.22 ± 0.64 vs 3.91 ± 0.57), and attenuated brain edema (84.61 ± 0.08% vs 85.29 ± 0.09%) after cerebral I/R. In addition, Pam3CSK4 pre-treatment preserved BBB function as evidenced by decreased leakage of serum albumin (0.528 ± 0.026 vs 0.771 ± 0.059) and Evans Blue (9.23 ± 0.72 μg/mg vs 12.56 ± 0.65 μg/mg) into brain tissue. Pam3CSK4 pre-treatment also attenuated the loss of the tight junction protein occludin in response to brain I/R injury. These results suggest that TLR2 is a new target of ischemic preconditioning in the brain and preconditioning with a TLR2 specific ligand will protect the brain from I/R injury.

To quantify the concurrent transduction capabilities of spatially distributed intrinsic cardiac neurons, the activities generated by atrial vs. ventricular intrinsic cardiac neurons were recorded simultaneously in 12 anesthetized dogs at baseline and during alterations in the cardiac milieu. Few (3%) identified atrial and ventricular neurons (2 of 72 characterized neurons) responded solely to regional mechanical deformation, doing so in a tightly coupled fashion (cross-correlation coefficient r = 0.63). The remaining (97%) atrial and ventricular neurons transduced multimodal stimuli to display stochastic behavior. Specifically, ventricular chemosensory inputs modified these populations such that they generated no short-term coherence among their activities (cross-correlation coefficient r = 0.21 ± 0.07). Regional ventricular ischemia activated most atrial and ventricular neurons in a noncoupled fashion. Nicotinic activation of atrial neurons enhanced ventricular neuronal activity. Acute decentralization of the intrinsic cardiac nervous system obtunded its neuron responsiveness to cardiac sensory stimuli. Most atrial and ventricular intrinsic cardiac neurons generate concurrent stochastic activity that is predicated primarily upon their cardiac chemotransduction. As a consequence, they display relative independent short-term (beat-to-beat) control over regional cardiac indexes. Over longer time scales, their functional interdependence is manifest as the result of interganglionic interconnections and descending inputs.

We examined whether blocking the MyD88 mediated pathway could protect myocardium from ischemia/reperfusion (I/R) injury by transfecting Ad5-dnMyD88 into the myocardium of rats (n = 8) 3 days before the hearts were subjected to ischemia (45 min) and reperfusion (4 h). Ad5-GFP served as control (n = 8). One group of rats was (n = 8) subjected to I/R without transfection. Transfection of Ad5-dnMyD88 significantly reduced infarct size by 53.6% compared with the I/R group (15.1 ± 3.02 vs 32.5 ± 2.59) while transfection of Ad5-GFP did not affect I/R induced myocardial injury (35.4 ± 2.59 vs 32.5 ± 2.59). Transfection of Ad5-dnMyD88 significantly inhibited I/R-enhanced NFκB activity by 50% and increased the levels of phospho-Akt by 35.6% and BCL-2 by 81%, respectively. Cardiac myocyte apoptosis after I/R was significantly reduced by 59% in the Ad5-dnMyD88 group. The results demonstrate that both inhibition of the NFκB activation pathway and activation of the Akt signaling pathway may be responsible for the protective effect of transfection of dominant negative MyD88.

Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. The study objective was to determine whether thoracic spinal dorsal column stimulation (SCS) modulates cardiac afferent sensory transduction of the ischemic ventricle. In anesthetized canines (n = 16), extracellular activity generated by 62 dorsal root ganglia (DRG) soma (T1-T3), with verified myocardial ischemic (MI) sensitivity, were evaluated with and without 20-min preemptive SCS (T1-T3 spinal level; 50 Hz, 90% motor threshold). Transient MI was induced by 1-min coronary artery occlusion (CAO) of the left anterior descending (LAD) or circumflex (LCX) artery, randomized as to sequence. LAD and LCX CAO activated cardiac-related DRG neurons (LAD: 0.15 ± 0.04-1.05 ± 0.20 Hz, P < 0.00002; LCX: 0.08 ± 0.02-1.90 ± 0.45 Hz, P < 0.0003). SCS decreased basal neuronal activity of neurons that responded to LAD (0.15 ± 0.04 to 0.02 ± 0.01 Hz, P < 0.006) and LCX (0.08 ± 0.02 to 0.02 ± 0.01 Hz, P < 0.003). SCS suppressed responsiveness to transient MI (LAD: 1.05 ± 0.20-0.03 ± 0.01 Hz; P < 0.0001; LCX: 1.90 ± 0.45-0.03 ± 0.01 Hz; P < 0.001). Suprathreshold SCS (1 Hz) did not activate DRG neurons antidromically (n = 10 animals). Ventricular fibrillation (VF) was associated with a rapid increase in DRG activity to a maximum of 4.39 ± 1.07 Hz at 20 s after VF induction and a return to 90% of baseline within 10 s thereafter. SCS obtunds the capacity of DRG ventricular neurites to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress, thereby contributing to its capacity to cardioprotect.NEW & NOTEWORTHY Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. This study determined that thoracic spinal column stimulation (SCS) obtunds the capacity of dorsal root ganglia ventricular afferent neurons to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress. This modulation does not reflect antidromic actions of SCS but likely reflects efferent-mediated changes at the myocyte-sensory neurite interface.