Cardioprotection and Kallikrein–kinin System in Acute Myocardial Ischaemia in Mice

Abstract

1. Acute myocardial ischaemia and reperfusion trigger cardioprotective mechanisms that tend to limit myocardial injury. These cardioprotective mechanisms remain for a large part unknown, but can be potentiated by performing ischaemic preconditioning or by administering drugs such as angiotensin-I-converting enzyme (kininase II) inhibitors (ACEI). 2. This brief review summarizes the findings concerning the role of tissue kallikrein (TK), a major kinin-forming enzyme, kinins and kinin receptors in the cardioprotection afforded by ischaemic preconditioning (IPC) or by pharmacological postconditioning by drugs originally targeted at the renin-angiotensin system, ACEI and type 1 angiotensin-II receptor blockers (ARB) in acute myocardial ischaemia. Myocardial ischaemia was induced by left coronary occlusion and was followed after 30 min by a 3 h reperfusion period (IR), performed in vivo in mice. The role of the kallikrein-kinin system (KKS) was studied by using genetically engineered mice deficient in TK gene and their wild-type littermates, or by blocking B1 or B2 bradykinin receptors in wild-type mice using selective pharmacological antagonists. 3. Ischaemic preconditioning (three cycles: 3 min occlusion/5 min reperfusion) enhances the ability of the heart of wild-type mice to tolerate IR. Tissue kallikrein plays a major role in the cardioprotective effect afforded by IPC, which is largely reduced in TK-deficient mice. The B2 receptor is the main kinin receptor involved in the cardioprotective effect of IPC. 4. Tissue kallikrein is also required for the cardioprotective effects of pharmacological postconditioning with ACEI (ramiprilat) or ARB (losartan), which are abolished for both classes of drugs in TK-deficient mice. The B2 receptor mediates the cardioprotective effects of these drugs. Activation of angiotensin-II type 2 (AT2) receptor is involved in the cardioprotective effects of losartan, suggesting a functional coupling between AT2 receptor and TK during angiotensin-II type 1 (AT1) receptor blockade. 5. The demonstration of a cardioprotective effect of the KKS in acute myocardial ischaemia involving TK and the B2 receptor and playing a major role in IPC or pharmacological postconditioning by ACEI or ARB, suggests a potential therapeutic approach based on pharmacological activation of the B2 receptor.

Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis

“…The beneficial effects of angiotensin-converting enzyme inhibition in hypertension, cardiovascular and renal disease can be partially attributed to kinin accumulation resulting from the activation of the B2 receptor [16,17] . Previous animal studies suggested that kallikrein/kinin protects against myocardial apoptosis after ischemia/reperfusion injury [18,19] . In our study, delivery of the kallikrein gene protected against cardiomyocyte apoptosis in SHRs; therefore, this gene could potentially be used to treat hypertension.…”

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion

“…Ventricular pressure and rate were recorded from a fluid-filled balloon tied into the left ventricle (isovolumic heart). Increasing doses of OK (1,2,4,8,16,32,64,128,256, 512 ng) were injected as a bolus into a port of the perfusion apparatus close to the coronary ostia. Subsequent injections were made only after blood pressure returned to baseline.…”

“…A number of observations have focused on Lys-BK as a potential mediator of endogenous cardiovascular protective mechanisms. This is due to the fact that KKS components are localized in the heart and in the vascular tissues (1)(2)(3)(4). Lys-BK is released during ischemia, causing beneficial cardiac effects and contributing to the cardioprotective effects of preconditioning (2)(3)(4).…”

“…This is due to the fact that KKS components are localized in the heart and in the vascular tissues (1)(2)(3)(4). Lys-BK is released during ischemia, causing beneficial cardiac effects and contributing to the cardioprotective effects of preconditioning (2)(3)(4). Lys-BK reduces arteriolar resistance after triggering several downstream events via www.bjournal.com.br Braz J Med Biol Res 42 (9) 2009 activation of B 2 receptors, a seven-transmembrane Gprotein-coupled receptor on endothelial cells, and initiating prostacyclin synthesis, with the formation of nitric oxide and smooth muscle hyperpolarization factor (1,2).…”

Helping the circulatory system heal itself: manipulating kinin signaling to promote neovascularization

“…Modulation of kininase expression and activity has been reported in several vascular pathologies [36][37][38][39]. Consequently, inhibition of ACE enhances kinin stability and promotes vascular sprouting in animal models as well as in human cardiovascular patients, partly via the B 2 R and partly via other mechanisms [13,9,[40][41][42]. Using angiotensin II receptor type 1 knockout mice, Li et al demonstrated the involvement of both kinin receptors and NO signaling in ACE inhibitor-mediated angiogenesis in hindlimb ischemia [9].…”