RAAS: A Convergent Player in Ischemic Heart Failure and Cancer

Abstract

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.

Keywords: cancer; heart failure; myocardial infarction; renin-angiotensin-aldosterone system.

Figure 1

Myocardial infarction and heart-failure-related events. Shortly after myocardial injury, an increase in AngII concentration occurs and induces an accumulation, differentiation, and exit of hematopoietic stem/precursor cells (HPSC) from the bone marrow to contribute to splenic myelopoiesis to supply the infarcted area of the immune cells. Cardiomyocyte necrosis releases signals of danger and induces the secretion of cytokines, chemokines, and adhesion molecules to allow the recruitment and infiltration of leukocytes (mainly monocytes) into the infarcted area. Monocytes exert a reparative response, phagocytosing the cellular debris, while it stimulates repair pathways by secreting pro-inflammatory cytokines through the binding of angiotensin-II (AngII) to type 1 angiotensin-II receptor (AT1R), which induces the phosphorylation of nuclear factor-kappa B (NF-kB). This induces a pro-inflammatory response mediated by tumor necrosis factor-alpha (TNF-α) or interleukin-1 beta (IL1ß) and drives inflammation. The modulation of inflammation in this repair phase includes fibroblast activation and healing mediated in part by renin-angiotensin- aldosterone system (RAAS). When this response becomes chronic, it leads to a pathological process called ventricular remodeling, characterized by progressive hypertrophy of myocytes and interstitial fibrosis, which in later stages involve progressive loss of myocytes through apoptosis, an exacerbated inflammatory response. The healing and the adverse remodeling of the infarcted ventricle ultimately underlie heart failure. This environment can lead to the secretion of certain factors into the circulation that are synthesized in various cell types in the heart, including cardiomyocytes, fibroblasts, smooth muscle, and vascular endothelial cells and other unknown factors. Image created with BioRender.com (Toronto, ON, Canada).

Figure 2

The endothelium in a normal and pathological state. The endothelium is a monolayer of cells that covers the interior of each major and minor vessel. A healthy endothelium has anti-inflammatory, anti-thrombotic properties and promotes vasodilation through nitric oxide (NO) release (left side). Cardiovascular risk factors such as obesity, diabetes and hypertension could promote a dysfunctional endothelium (right side) that is characterized by a decrease in NO release as well as an increment in reactive oxygen species (ROS) and a pro-inflammatory activity mediated by AngII/AT1R signaling, which activates NF-κB and, consequently, the expression of cytokines, chemokines, and adhesion molecules: interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1) by endothelial cells. Then, myeloid cells such as monocytes migrate and infiltrate towards the aortic walls (where they become macrophages) contributing to the endothelial dysfunction by producing tumor necrosis factor-alpha (TNF-α), IL-6, and MCP-1. Image created with BioRender.com, Toronto, ON, Canada.

Figure 3

Role of RAAS in the tumor microenvironment. Immune cells can infiltrate tumors and differentiate into tumor-associated macrophages (TAM) derived mainly from circulating monocytes and are attracted to the tumor by chemokines. TAMs can stimulate tumor cell proliferation, angiogenesis, invasion and metastasis. Additionally, tumor microenvironment (TME) can influence the phenotype of circulating monocytes such as the Ly6C^high monocyte subset, giving them an immunosuppressive activity and a decreased responsiveness to inflammatory stimuli before their infiltration intoTME. Angiotensin-II (AngII) plays a relevant role in macrophage-mediated chronic inflammation, increasing macrophage progenitors and supplying of TAMs. Additionally, endothelial cells (EC) can promote pro-inflammatory signaling, favoring spontaneous metastasis in adjacent tumors through an aberrant expression of pro-inflammatory cytokines, extracellular matrix, alterations in the leukocyte adhesion process, increasing vascular cell adhesion molecule-1 (VCAM-1) and abnormal responses to oxidative stress. In ECs, AngII/AT1R signaling generates a pro-angiogenic response mediated by vascular endothelial growth factor (VEGF). AngII signaling activates TNF-α and NF-κB and upregulates pro-inflammatory endothelial chemokines. AngII has been reported to be able to promote VCAM-1 expression and enhance adhesion, growth, angiogenesis, and the inflammatory microenvironment through AT1R in hepatocellular carcinoma. It has been reported that angiogenesis promotes tumor cell metastasis. Image created with BioRender.com, Toronto, ON, Canada.