Tumor Necrosis Factor-α–Mediated Downregulation of the Cystic Fibrosis Transmembrane Conductance Regulator Drives Pathological Sphingosine-1-Phosphate Signaling in a Mouse Model of Heart Failure

Abstract Background: The mechanism by which hypertriglyceridemia (HTG) leads to pancreatitis is not clear. We sought to determine whether the genes involved in pancreatic ductal or acinar cell injury, including the cationic trypsinogen gene [protease, serine, 1 (trypsin 1) (PRSS1)], the pancreatic secretory trypsin inhibitor gene [serine peptidase inhibitor, Kazal type 1 (SPINK1)], the cystic fibrosis transmembrane conductance regulator gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) (CFTR)], and inflammation genes such as tumor necrosis factor [tumor necrosis factor, TNF superfamily, member 2 (TNF)] are associated with hyperlipidemic pancreatitis (HLP) in patients with HTG. Methods: We performed genetic analysis of 126 HTG patients in Taiwan (46 with HLP and 80 without HLP). The entire coding and intronic regions of the PRSS1, SPINK1, and CFTR genes were identified by heteroduplex analysis techniques and were confirmed by sequencing analysis. The presence of 125G/C, 1001 + 11C>T, 1540A>G (Met470Val), 2694T>G, and 4521G>A in CFTR, the presence of 272C>T in SPINK1, and TNF promoter polymorphisms (nucleotide positions 1031, 863, 857, 308, and 308) were measured by direct sequencing. Results: Of the 126 HTG patients, 13 (10.3%) carried a CFTR mutation. No PRSS1 or SPINK1 mutations were detected in our patients or in HTG controls. The CFTR gene mutation rates in HTG with and without HLP were 26.1% (12 of 46) and 1.3% (1 of 80), respectively (P <0.0001). The CFTR gene mutations were all Ile556Val. A multivariate analysis of HTG patients indicated that triglycerides, CFTR 470Val, and TNF promoter 863A were independent risk markers for HLP. Conclusions: This genetic study is the first one to address the association of HLP with the CFTR mutation/variant/haplotype and TNF promoter polymorphism in a Chinese HTG population. The results suggest that the occurrence of HLP is multifactorial and polygenic.

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Effects of amiodarone on tumor necrosis factor-α levels in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

The American Journal of Cardiology ◽

10.1016/s0002-9149(98)00874-1 ◽

1999 ◽

Vol 83 (3) ◽

pp. 388-391 ◽

Cited By ~ 20

Author(s):

Hakan Oral ◽

Susan G Fisher ◽

William P Fay ◽

Steven N Singh ◽

Ross D Fletcher ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Tumor Necrosis Factor ◽

Dilated Cardiomyopathy ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Idiopathic Dilated Cardiomyopathy ◽

Factor Α ◽

Necrosis Factor

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Abstract P317: Sex Differences in the Hemodynamic and Sympathetic Responses to Centrally Administered Tumor Necrosis Factor-α in Rats

Hypertension ◽

10.1161/hyp.70.suppl_1.p317 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Shun-Guang Wei ◽

Yang Yu ◽

Robert B Felder

Keyword(s):

Heart Failure ◽

Sex Differences ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Female Rats ◽

Male Rats ◽

Tnf Α ◽

Estrogen Effect ◽

Factor Α ◽

Necrosis Factor

Introduction: Accumulating evidence indicates that sex differences exist in the clinical and experimental outcomes of various cardiovascular diseases. In addition to its protective effect on renin-angiotensin system activity, estrogen has an anti-inflammatory influence. The central actions of pro-inflammatory cytokines (PICs) contribute significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. In male adult rat, central administration of PICs induces substantial increases in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA), and blocking PICs reduces sympathetic excitation in experimental models of hypertension and heart failure. Whether PICs have similar central sympatho-excitatory effects in the female rat remains unknown. Hypothesis: We hypothesized that female rats may be protected from the central cardiovascular and autonomic effects of PICs. Methods: Urethane anesthetized male and female Sprague Dawley rats (10-12 weeks) underwent an intracerebrovascular (ICV) injection of the prototypical PIC tumor necrosis factor-α (TNF-α, 100 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were continuously recorded for 4-5 hours. Results: In male rats (n=6), ICV TNF-α induced a dramatic and long-lasting increase (*p<0.001 vs. baseline) in BP (23.1 ± 2.5*), HR (82 ± 8*) and RSNA (109.5 ± 4.3 %*), that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In the female rats (n=6), ICV TNF-α elicited significantly (p<0.05) smaller increases (*p<0.001 vs. baseline) in BP (14.8 ± 1.8*), HR (55 ± 6*) and RSNA (78.5 ± 6.3*), compared with the male rats. Conclusion: These data demonstrate a sex difference in the cardiovascular and sympathetic responses to centrally administered PICs. Whether the observed differences can be explained by an estrogen effect on TNF-α signaling per se or by an estrogen effect on TNF-α-induced renin-angiotensin activity remains to be determined. However, a reduced response of female rats to central inflammation may be an important contributor to sex differences in pathophysiology of hypertension and heart failure.

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Abstract P136: Effects Of Sex Hormones On The Hemodynamic And Sympathetic Responses To Centrally Administered Tumor Necrosis Factor-α In Rats

Hypertension ◽

10.1161/hyp.76.suppl_1.p136 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Yiling Cao ◽

Baojian Xue ◽

Yang Yu ◽

Alan K Johnson ◽

Shun-Guang Wei

Keyword(s):

Heart Failure ◽

Tumor Necrosis Factor ◽

Sex Hormones ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Female Rats ◽

Tnf Α ◽

Sympathetic Responses ◽

Factor Α ◽

Necrosis Factor

Inflammation plays an important role in the pathophysiology of cardiovascular dysfunction and neurohumoral excitation in heart failure and hypertension. Growing evidence has demonstrated significant sex differences in the inflammatory response and immune processes, with estrogen exerting an anti-inflammatory effects and testosterone potentially having pro-inflammatory influence. We previously reported that central administration of tumor necrosis factor-α (TNF-α) elicited different effects on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male and female rats. Whether the sex steroids estrogen and testosterone contribute to the observed differences in TNF-α-induced hemodynamic and sympathetic responses remains unknown. We hypothesized that estrogen protects against TNF-α-induced sympathetic excitation and pressor responses while testosterone enhances these excitatory outcomes in response to TNF-α. Female or male Sprague Dawley rats (10-12 weeks) anesthetized with ketamine plus xylazine underwent bilateral ovariectomy or castration, respectively, 2 weeks prior to study. Sham-operated (Sham) female or male animals served as controls. TNF-α (100 ng) was administered intracerebroventricularly (ICV). BP (mmHg), HR (bpm) and RSNA (% change) were recorded in urethane anesthetized rats. In ovariectomized female rats (n=6), ICV TNF-α induced significantly (*p<0.05 vs. Sham) larger increases in BP (19.3 ± 1.4* vs. 12.8 ± 1.2 ), HR (76.3 ± 4.8* vs. 51.5 ± 4.3) and RSNA (104.8 ± 6.9* vs. 72.4 ± 5.1), compared with Sham-female rats, that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In castrated male rats (n=6), ICV TNF-α-elicited significantly smaller increases in BP (15.2 ± 1.3* vs. 21.8 ± 1.6), HR (57.7 ± 4.2* vs. 82.6 ± 4.1) and RSNA (72.6 ± 4.3* vs. 110.3 ± 4.7), compared with Sham-male animals. These data indicate a distinct role of sex hormones estrogen and testosterone in central inflammation-driven cardiovascular and sympathetic activation and suggest a protective effect of estrogen and a harmful effect of testosterone in the development of hypertension and heart failure.

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