Cardiovascular
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Browsing Cardiovascular by Author "Fairley, Amber"
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Item Alteration of Inflammatory Profile following Activation of a Neuroimmune Pathway(2016-03-23) Mathis, Keisa W.; Fairley, Amber; Patel, MaitrybenAbstract Hypertension is estimated to cause 7.5 million deaths worldwide and is a major risk factor for stroke, renal failure, and heart failure, all of which may be potentially fatal. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder with a high prevalence of hypertension. Inflammatory cytokines have been shown to promote the development of hypertension in recent studies. Other studies suggest that acute stimulation of an innate, vagally-mediated, neuro-immune pathway (the cholinergic anti-inflammatory pathway) suppresses the production of inflammatory mediators in the spleen. It is unknown whether chronic stimulation of this pathway is capable of reducing inflammation, and ultimately blood pressure during SLE. Purpose (a): The purpose of this study was to evaluate the effectiveness of stimulation of the cholinergic anti-inflammatory pathway on reducing inflammation in SLE. We hypothesized that pharmacological stimulation of the vagus nerve with CNI-1493 would suppress splenic cytokine release, thereby reducing systemic inflammation. Methods (b): CNI-1493 (8 mg/kg/2swk, IP) or vehicle (saline) was administered twice a week for 4 weeks, starting at 30 weeks of age in female SLE (NZBWF1) and control mice (NZW). At 34 weeks, animals were euthanized and tissues were collected in order to examine splenic and renal inflammation. The spleen and kidney were homogenized using RIPA buffer and the cytokine TNF-a was evaluated using Western blot in these tissues. Results (c): TNF-a expression (normalized to b-actin) was increased in the spleen (36.9±8.7 vs. 22.5±2.8; p=0.02) and renal cortex (8.4±0.4 vs. 3.7±0.5; p=0.03) of SLE mice compared to controls. CNI-1493 had no significant effect on spleen TNF (35.9±4.3), however exacerbated renal cortical TNF (12.5±2.2) in SLE mice. Conclusions (d): Although the results did not support our hypothesis, the data are preliminary and we suspect additional studies are needed to determine the ability of pharmacological stimulation of the vagus nerve to reduce inflammation in SLE mice. Such therapy could potentially benefit hypertensive SLE patients, since chronic inflammation has recently been linked to the development of the disease.Item Chronic Vagus Nerve Stimulation Attenuates Renal Inflammation in Autoimmune-Induced Hypertension(2016-03-23) Fairley, Amber; Maloy, Charles; Mathis, Keisa W.; Pham, GraceChronic renal inflammation has been implicated in the pathogenesis of hypertension, which identifies the autoimmune disease systemic lupus erythematosus (SLE) as a compelling disease model. The cholinergic anti-inflammatory pathway (CAP) is a vagally mediated neuroimmune pathway that, when impaired, may facilitate the development of chronic inflammation. While stimulation of the CAP attenuates inflammation in various models of inflammatory disease, it is unclear whether the pathway is impaired in SLE, or whether its stimulation is protective. We hypothesized that pharmacological activation of the CAP at the level of the vagus nerve would decrease renal inflammation and therefore blood pressure in a hypertensive SLE mouse model. Initially, female SLE (NZWF1) and control (NZW) mice were administered the efferent vagal stimulant, CNI-1493 (Semapimod hydrochloride; 8 mg/kg IP) or saline twice per week for 4 weeks starting at 30 weeks of age. SLE mice had 1143±439% (pItem Improvement in Blood Pressure and Renal Injury Following Vagal Nerve Stimulation(2016-03-23) Fairley, Amber; Mathis, Keisa W.; Pham, Grace; Maloy, CharlesPurpose: The concept that autoimmunity and its subsequent inflammation could play a role in the pathogenesis of hypertension and its end-organ damage has recently been supported by many studies. Recent studies have proposed a novel pathway, the cholinergic anti-inflammatory pathway, which may combat this inflammation and prevent the subsequent damage. Stimulation of the vagus nerve has been shown to reduce inflammation via this pathway. Systemic Lupus Erythematosus (SLE), an autoimmune disease with a high prevalence of hypertension, provides an appropriate model to test whether stimulation of this pathway can combat chronic inflammation and hypertension. We tested the hypothesis that pharmacological stimulation of the vagus nerve reduces blood pressure and improves renal injury and function in SLE mice (NZBWF1). Methods: Starting at 30 weeks of age, female SLE and control (NZW) mice were treated twice per week over four weeks with CNI1493 (Semapimod hydrochloride; 8 mg/kg, IP), which has been shown to stimulate the vagus nerve. Saline was used as the vehicle treatment. After treatment, a catheter was placed in the carotid artery to measure mean arterial pressure. Renal blood flow (mL/min*g kidney weight) was measured using a flow probe and renal vascular resistance was calculated (mmHg*min*g kidney weight/mL) as indices of renal function. Results: Mean arterial pressure (mmHg) was higher in SLE mice compared to controls (143±11 vs. 116±4; p=0.003; n=3 5/group). Treatment with CNI1493 attenuated the development of hypertension in the SLE mice (130 ± 4), but did not alter mean arterial pressure in controls (119 ± 5). Renal injury in the form of albuminuria (albumin excretion rate; μg/day) was increased in SLE mice compared to controls (4409±2519 vs. 4 ± 1; p=0.002; n =36/group). Albumin excretion rate was diminished in CNI 1493treated SLE mice (420±410; p = 0.008). CNI1493 treated SLE mice had higher renal blood flow (3.0 vs. 2.5±0.1mL/min*g; n=1 2/group) and lower renal vascular resistance (21.9 vs. 23.9±1mmHg*min*g/mL; n=12/group) compared to SLE mice treated with saline. Conclusion: These data suggest that stimulation of the vagus nerve may protect the kidney and prevent SLE hypertension; however, future studies are warranted to determine how this occurs. Taken together, our findings suggest that the vagallymediated cholinergic antiinflammatory pathway plays a mechanistic role in the development hypertension in the setting of chronic inflammation.