Treatment of Experimental Myocarditis via Modulation of the Renin-Angiotensin System

Abstract

The renin-angiotensin system is primarily responsible for regulating vascular tone. Drugs that inhibit this pathway, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, are widely used to treat hypertension and a variety of cardiomyopathies. Recent studies have shown that, in addition to reducing blood pressure, these drugs also modulate inflammation, adhesion molecule expression, and fibrosis. To assess the therapeutic potential of these inhibitory agents for the treatment of inflammatory heart disease, the drugs have been tested in experimental models of infectious and autoimmune myocarditis. This review summarizes the results of studies examining the efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists for the treatment of mouse models of virus-induced and parasite-induced myocarditis, as well as autoimmune cardiomyopathy. The collective results strongly support the use of renin-angiotensin modulation for the treatment of myocarditis. Importantly, this therapeutic approach seems to downregulate autoimmunity without causing immune suppression which may enhance the survival of the disease-initiating infectious agent.

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

“…Moreover, AngII modulates the inflammatory response by increasing T-cell activation, homing marker expression and cytokine production [201]. Conversely, ACEI therapy, which has recently been suggested in the treatment of sepsis [202], is able to dampen the immune response, decreasing the synthesis of inflammatory cytokines [203] and the expression of the MHC molecule [204]. Finally, experimental and clinical use of ACEI has been shown to increase both IGF-1 tissue bioactivity [205] and serum [206,207] levels.…”

Highly selective hydrolysis of kinins by recombinant prolylcarboxypeptidase

“…The upregulation of both the RAS and KKS leading to subsequent physiological and cellular responses such as inflammation, cell growth and differentiation, and angiogenesis following tissue injury, support the importance of these systems as potential targets for therapeutic intervention in a variety of diseases[3–5]. The activation of RAS results in the generation of bioactive angiotensin peptides with hypertensive[6], antihypertensive[7], immunostimulating[8;9] and cytomodulatory[10;11] activities. The major metabolic end products released by RAS that induce vasoconstriction and thrombotic events are angiotensin II (Ang II) and angiotensin III (Ang III)[12].…”

Molecular mechanisms of host cell invasion by Trypanosoma cruzi

“…The generation of kinins by cruzipain results in bradykinin receptor (B 2 R)-mediated signaling through PLC and IP 3 -kinase to release ER-bound calcium, opposed by the actions of the kininases (angiotensin converting enzyme-ACE) [14, 86, 87]. Evidence suggests that the anti-inflammatory properties of ACE inhibition is useful to modulate cardiac inflammation in Chagas [87, 88], as it does in models of experimental autoimmune myocarditis [89]. Surface signaling through other bradykinin receptors (B 1 R) by the actions of kininase I, support invasion [90], and the action of oligopeptidase B on its substrate is thought to generate an agonist for host cell calcium release through adenylate cyclase and phospholipase C [91].…”