Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease

Abstract

Purpose of review Drugs targeting the renin-angiotensin system (RAS), namely angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious Ang II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). Recent findings Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently-discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from [Ang-(1-12)]. The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. [Ang-(1-12)] expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Summary Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously-unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the [Ang-(1-12)]/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

Role of Tissue Renin-angiotensin System and the Chymase/angiotensin-( 1-12) Axis in the Pathogenesis of Diabetic Retinopathy

“…Thus, the therapeutic approaches to prevent the progression of DR in diabetic people using the ACE inhibitor require further exploration. Our recent studies show that the chymase/Ang-(1-12) axis is primarily responsible for the generation of cellular Ang II rather than the ACE [81, 82]. These findings further suggest that the combination therapy (chymase and ACE inhibitions), compared to ACE inhibition alone, might be more beneficial to prevent the DR progression in diabetic people.…”

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

“…This conclusion is reminiscent of the report made by the Blood Pressure Lowering Treatment Trialists’ Collaboration group who reported no evidence for differences among drug classes for major cardiovascular events [101]. While many arguments may be posited as to the reasons for this disconnect, we have proposed that incomplete blockade of Ang II pathological actions is due to the failure of RAAS inhibitors to access intracellular proteins accounting for canonical and non-canonical mechanisms of Ang II formation [19–21, 39]. …”

“…The apparent limited ability of ACE inhibitors to maintain a consistent suppression of plasma and tissue Ang II levels in part explains why re-analysis of clinical benefits associated with ACE inhibition from robust meta-analysis of the currently reported clinical trials documents a higher than expected residual risk of clinical events [18]. As reviewed in Reyes et al [21], the relative risk reduction (RR) achieved with ACE inhibitors for the treatment of hypertension, post-myocardial infarction, and HF averaged 27% in major clinical trials. In keeping with these findings, Baker’s et al [14] analysis of 7 clinical studies that included 32,559 participants showed a RR of 0.87 [95% CI, 0.81 to 0.94] and 0.83 [CI, 0.73 to 0.94] for total mortality and nonfatal myocardial infarction, respectively.…”

“…First, tissue mechanisms associated with the cardiac and vascular adaptive response to hypertension, coronary heart disease and HF may be associated with or caused by activation of intracrine mechanisms of Ang II formation and action [20, 21, 173, 174, 254–257]. Biochemical mechanisms for angiotensins generation and receptor signaling are present within the cellular environment including nuclei mitochondria [258–260].…”

“…Instead, we will underscore one potential explanation for the fact that clinical outcome studies using a direct renin inhibitor, ACE inhibitors or ARBs have demonstrated benefits that are less than what would have been expected. Those wishing to delve more deeply on the arguments presented in this review can access the enclosed references [14–21]. …”