Hypertension augments cardiac Toll-like receptor 4 expression and activity.
Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; 4, 8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L-NAME (N(ω)-nitro-L-arginine-methylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-α and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg(-1) per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg(-1) per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg(-1) per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model.
Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Ruth
R
Eissler
Christoph
C
Schmaderer
Krisztina
K
Rusai
Louisa
L
Kühne
Daniel
D
Sollinger
Tobias
T
Lahmer
Oliver
O
Witzke
Jens
J
Lutz
Uwe
U
Heemann
Marcus
M
Baumann
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000188:drug therapy; D018932:Chemokine CCL2 / Q000096:biosynthesis; D006497:Heparan Sulfate / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D018932:Chemokine CCL2; D006497:Heparan Sulfate; D015850:Interleukin-6; D019331:NG-Nitroarginine Methyl Ester; D017257:Ramipril; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C491766:Ccl2 protein, rat