Involvement of chymase-mediated angiotensin II generation in blood pressure regulation

Li, Ming; Liu, Ke; Michalicek, Jan; Angus, James A.; Hunt, John; Dell’Italia, Louis J.; Feneley, Michael P.; Graham, Robert M.; Husain, Ahsan

doi:10.1172/jci20805

Cited by 44 publications

(28 citation statements)

References 33 publications

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“…In mice, a chronic deficiency of vascular chymase is not associated with any compensatory increase in vascular ACE activity (Li et al . ); thus, in these animals the total vascular Ang II‐forming capacity of the vessel is not normalized. Our data suggest that although ACE is essential for Ang II synthesis in blood plasma, chymase provides an important mechanism for its formation in tissues, especially in pathological conditions.…”

Section: Discussionmentioning

confidence: 98%

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Roszkowska-Chojecka

Walkowska

Gawryś

et al. 2015

Experimental Physiology

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New Findings r What is the central question of this study?We examined, in hypertensive rats, whether the angiotensin-converting enzyme-independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. r What is the main finding and its importance?The results suggest that chymostatin-sensitive enzymes diminish vascular tone in renal and extrarenal vascular beds. Chymase or similar chymostatin-sensitive enzymes have a significant role in the synthesis of angiotensin II in different tissues but do not control blood pressure in the short term, similarly in salt-dependent or Goldblatt-type rat hypertension. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing the angiotensin II content in the kidney.Chymase is presumed to be a crucial enzyme of the non-angiotensin-converting enzyme pathway of angiotensin II (Ang II) generation in tissues, a process involved in vascular remodelling and development of hypertension. We examined the role of chymase in hypertension induced by exposure of uninephrectomized rats to high dietary salt intake (UNX HS) and in the Goldblatt renal artery stenosis (two-kidney, one-clip) model. In acute experiments with anaesthetized rats of either model, chymostatin at 2 mg kg −1 h −1 or 0.05% DMSO solvent was infused i.v. Mean arterial blood pressure, heart rate, iliac blood flow (a measure of hindlimb perfusion), total renal blood flow and intrarenal regional perfusion (laser-Doppler technique) were measured continuously, along with the glomerular filtration rate and renal excretion. In both models, chymase blockade distinctly decreased plasma and tissue Ang II without lowering mean blood pressure or consistently altering the other functional parameters measured. Unexpectedly, in Goldblatt hypertensive rats the blockade increased the renal and hindlimb vascular resistances by 51 and 33%, respectively (P < 0.05). In UNX HS hypertensive rats, chymase blockade abolished the solvent-induced decrease in outer medullary blood flow. We conclude that chymase or similar chymostatin-sensitive enzyme(s) has a significant role in the synthesis of Ang II in different tissues but does not participate in short-term control of blood pressure in salt-dependent or Goldblatt-type rat hypertension. In the Goldblatt model, chymase appeared to reduce the renal and hindlimb vascular resistances by an unknown mechanism. In salt-dependent hypertension,

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Section: Discussionmentioning

confidence: 98%

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Roszkowska-Chojecka

Walkowska

Gawryś

et al. 2015

Experimental Physiology

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“…The body of experimental evidence that chymases are important in cardiovascular diseases, including regulation of blood pressure (121), is large and expanding. Much of this evidence, which has been reviewed elsewhere (122–124), is beyond the scope of this review.…”

Section: Proinflammatory Actions Of Mast Cell Serine Peptidasesmentioning

confidence: 99%

Mast cell tryptases and chymases in inflammation and host defense

Caughey

2007

Immunological Reviews

389

329

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Tryptases and chymases are the major proteins stored and secreted by mast cells. The types, amounts, and properties of these serine peptidases vary by mast cell subtype, tissue, and mammal of origin. Membrane-anchored gamma-tryptases are tryptic, prostasin-like, type I peptidases that remain membrane attached on release and act locally. Soluble tryptases, including their close relatives, mastins, form inhibitor-resistant oligomers that act more remotely. Befitting their greater destructive potential, chymases are quickly inhibited after release, although some gain protection by associating with proteoglycans. Most chymase-like enzymes, including mast cell cathepsin G, hydrolyze chymotryptic substrates, an uncommon capability in the proteome. Some rodent chymases, however, have mutations resulting in elastolytic activity. Secreted tryptases and chymases promote inflammation, matrix destruction, and tissue remodeling by several mechanisms, including destroying procoagulant, matrix, growth, and differentiation factors and activating proteinase-activated receptors, urokinase, metalloproteinases, and angiotensin. They also modulate immune responses by hydrolyzing chemokines and cytokines. At least one chymase protects mice from intestinal worms. Tryptases and chymases can also oppose inflammation by inactivating allergens and neuropeptides causing inflammation and bronchoconstriction. Thus, like mast cells themselves, mast cell serine peptidases play multiple roles in host defense, and any accounting of benefit versus harm is necessarily context specific.

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“…Chymase is considered to be responsible for >80% of tissue Ang II formation in the human heart and >60% of that in arteries [126]. Therefore, chymase has been implicated in the pathogenesis of cardiovascular diseases, including atherosclerosis and hypertension [127,128]. Recently, it was reported that homocysteine may increase mast cell chymase expression and activity through the mechanism of oxidative stress [129,130].…”

Section: Strategies Of Stroke Prevention In Patients With Hypertensionmentioning

confidence: 99%

From Hypertension to Stroke: Mechanisms and Potential Prevention Strategies

Zhou

Cai

2011

CNS Neuroscience & Therapeutics

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SUMMARYStroke is a major cause of disability and death worldwide. Prevention aimed at risk factors of stroke is the most effective strategy to curb the stroke pandemic. Hypertension is one of the most important risk factors for stroke. Despite the substantial evidence of the benefits of lowering blood pressure, conventional treatment does not normalize the burden of major cardiovascular events in patients with hypertension. Fully understanding the factors involved in the hypertension-induced stroke helps to develop new strategies for stroke prevention. Antihypertensive therapies selected should have positive blood pressureindependent effects on stroke risk. This review summarizes the factors involved in the hypertension-induced stroke, such as oxidative stress, inflammation, and arterial baroreflex dysfunction, and potential strategies for its prevention, therefore, provides clues for clinicians.

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Involvement of chymase-mediated angiotensin II generation in blood pressure regulation

Cited by 44 publications

References 33 publications

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Mast cell tryptases and chymases in inflammation and host defense

From Hypertension to Stroke: Mechanisms and Potential Prevention Strategies

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