Management of inflammation in cardiovascular diseases

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality world-wide. Recently, the role of inflammation in the progression of diseases has significantly attracted considerable attention. In addition, various comorbidities, including diabetes, obesity, etc. exacerbate inflammation in the cardiovascular system, which ultimately leads to heart failure. Furthermore, cytokines released from specialized immune cells are key mediators of cardiac inflammation. Here, in this review article, we focused on the role of selected immune cells and cytokines (both pro-inflammatory and anti-inflammatory) in the regulation of cardiac inflammation and ultimately in cardiovascular diseases. While IL-1β, IL-6, TNFα, and IFNγ are associated with cardiac inflammation; IL-10, TGFβ, etc. are associated with resolution of inflammation and cardiac repair. IL-10 reduces cardiovascular inflammation and protects the cardiovascular system via interaction with SMAD2, p53, HuR, miR-375 and miR-21 pathway. In addition, we also highlighted recent advancements in the management of cardiac inflammation, including clinical trials of anti-inflammatory molecules to alleviate cardiovascular diseases.

Keywords: Cardiac diseases; Cytokines; Immune cells; Inflammation; Interferons; TNFα.

Fig. 1.. IL-10 regulation of cardiac cell biology:

IL-10, an anti-inflammatory cytokine, is secreted from different immune and lymph cells, which inhibits isoproterenol (ISO)-induced hypertrophy and TNFα-mediated signaling, including inflammation. ISO-mediated activation of G-protein coupled receptor (GPCR) results in generation of Ras-GTP from Ras-GDP. Ras-GTPase activates inhibitor of nuclear factor-κB (IκB) kinase (IKK) via p38 which results in upregulation of hypertrophic and inflammatory genes expression. Activation of IL-10 receptor 1 (IL-10R1) and 2 (IL-10R2) by IL-10, results in phosphorylation of STAT3 which inhibits p38 and IKK, thus blunting ISO-induced hypertrophic signal in the cardiac muscle cells. Furthermore, IL-10 also protects endothelial cells from inflammatory injury following damage to the carotid artery and inhibits intimal hyperplasia. In vitro, IL-10 inhibits TNFα induced-apoptosis and cell cycle arrest of endothelial cells, and adhesion of monocytes to endothelial cells.

Fig. 2:. IL-1β augments cardiac inflammation.

Inflammation augments NFkB mediated inflammatory genes expression, including Nlrp3 (inflammasome). Further, inflammasome-mediated caspase-1 activation produces IL-1β from pro-IL-1β (127). Neutrophils help in the production of IL-1β via releasing protease (128). In general, IL-1β via acting through its receptor (IL-1R) activates NFkB and AP1 signaling, which leads to the generation of inflammatory mediators (iNOS, IL-6, TNFα, MCP1, VCAM1, COX2, etc.), apoptosis (p53, Bak, etc.), hypertrophy (ANP, βMHC, etc.) and fibrosis (MMPs, TGFβ, ECM, etc.) in heart (–131). VCAM1, MCP1 and COX2 derived lipids help in the leucocyte adhesion and favors blood clot formation via their interaction with endothelial cell (131). Anakinra (IL-1R blocker) and antibodies against IL-1β (gevokizumab and canakinumab) inhibits inflammatory activity of IL-1β.

Fig. 3.. IL-10 helps in cardiac regeneration and protects the heart via alleviating inflammation and apoptosis.

IL-10 inhibits miR-375 which upregulates PDK1/AKT pathway and increases angiogenesis and cell survival of bone marrow angiogenic progenitor cells (BMAPC). The miR-375 inhibition in BMAPC increases its survival after transplantation in the heart following MI. This suggests how IL-10 can protect the heart following MI via downregulating miR-375. Following MI, the level of SDF-1 decreases which reduces bone marrow progenitor cell mobilization and homing to the heart that impairs cardiac regeneration. Exogenous administration of IL-10 increases the expression of SDF-1 which helps in the movement of bone marrow progenitor cells and improves cardiac function in an infarcted heart. The deletion of HuR protein in macrophage reduces the level of TNFα, p53 and TGF-β following inflammatory insult. Upon binding of HuR to AU-rich elements (AREs) in the 3 untranslated regions of mRNA of inflammatory cytokine, including IL-1β and TNFα, stabilizes the cytokines which augments cardiac inflammation. HuR also promotes apoptosis via p53 signaling and augments fibrosis via activation of TGF-β. IL-10 inhibits HuR and, therefore, reduces cardiac inflammation, apoptosis and fibrosis. In IL-10 KO mice, the deletion of HuR alleviates cardiac dysfunction. IL-10 also inhibits the movement of bone marrow fibroblast progenitor cells following pressure overload-induced hypertrophy and minimizes cardiac fibrosis.