Ca2+/Calmodulin-dependent kinase II delta B is essential for cardiomyocyte hypertrophy and complement gene expression after LPS and HSP60 stimulation in vitro

Abstract

Inflammation plays an important role in the development of cardiovascular diseases (CVDs), suggesting that the immune system is a target of therapeutic interventions used for treating CVDs. This study evaluated mechanisms underlying inflammatory response and cardiomyocyte hypertrophy associated with bacterial lipopolysaccharide (LPS)- or heat shock protein 60 (HSP60)-induced Toll-like receptor (TLR) stimulation and the effect of a small interfering RNA (siRNA) against Ca 2+ /calmodulin-dependent kinase II delta B (CaMKIIδB) on these outcomes. Our results showed that treatment with HSP60 or LPS (TLR agonists) induced cardiomyocyte hypertrophy and complement system C3 and factor B gene expression. In vitro silencing of CaMKIIδB prevented complement gene transcription and cardiomyocyte hypertrophy associated with TLR 2/4 activation but did not prevent the increase in interleukin-6 and tumor necrosis factor-alfa gene expression in primary cultured cardiomyocytes. Moreover, CaMKIIδB silencing attenuated nuclear factor-kappa B expression. These findings supported the hypothesis that CaMKIIδB acts as a link between inflammation and cardiac hypertrophy. Furthermore, the present study is the first to show that extracellular HSP60 activated complement gene expression through CaMKIIδB. Our results indicated that a stress stimulus induced by LPS or HSP60 treatment promoted cardiomyocyte hypertrophy and initiated an inflammatory response through the complement system. However, CaMKIIδB silencing prevented the cardiomyocyte hypertrophy independent of inflammatory response induced by LPS or HSP60 treatment.

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

“…There is a study from our group using interference RNA (RNAi) to block the expression of CaMKIIδ. It demonstrates that CaMKIIδ is fundamental for cardiomyocyte hypertrophy; once blocking the expression, the LPS-induced hypertrophy is reverted (Cruz Junho et al, 2019).…”

“…Ca 2+ signaling is involved in epigenetic regulation, and the study of its signaling can contribute to the development of new therapeutic strategies (Awad et al, 2015;Puri, 2020). CaMKIIδ has been already described as fundamental for cardiac hypertrophy development (Cruz Junho et al, 2019). This mechanism occurs after CaMKIIδ selectively phosphorylates HDAC4.…”

Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

“…However, the application of extracellular HSP70 antagonism in mice revealed that blockade of combining HSP70 with TLR4 decreases macrophage infiltration and inflammatory cytokine expression, thereby attenuating pressure overload-induced cardiac hypertrophy and fibrosis. Similarly, HSP60 was shown to be an agonist of TLR4, where it stimulates the innate immune system and induces cardiomyocyte hypertrophy and upregulates hypertrophic markers such as brain natriuretic peptide (BNP) and α-actin (45). In addition, it is interesting to note that the complement system is also activated by HSP60, as evidenced by its ability to induce inflammation at the adaptive immunity level that causes cardiac hypertrophy (45).…”

“…Similarly, HSP60 was shown to be an agonist of TLR4, where it stimulates the innate immune system and induces cardiomyocyte hypertrophy and upregulates hypertrophic markers such as brain natriuretic peptide (BNP) and α-actin (45). In addition, it is interesting to note that the complement system is also activated by HSP60, as evidenced by its ability to induce inflammation at the adaptive immunity level that causes cardiac hypertrophy (45). Similarly, HSP60 was shown to exert cardioprotective and anti-apoptotic effects on animal models of myocardial ischemia/reperfusion injury (54), but HSP60 and TLR4 overexpression promote their interaction in hypertrophic myocardium, which may be a crucial event to permit harmful effects of HSP60 (55).…”

Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology

“…Gut dysbiosis and increased gut permeability are associated with the transfer of gut bacteria or tiny fragments of partially digested food over the gut barrier, leading to raised levels of circulating lipopolysaccharide (LPS), that acts on the immune system to heighten pro-inflammatory cytokines and ROS [46]. LPS activation of the toll-like receptor (TLR)4 is sufficient to drive LVH [47]. The association of chronic and repetitive stress with anxiety and depression seems at least partially mediated by gut dysbiosis and increased gut permeability [48].…”