Inhibition of JNK and p38 MAPK‐mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin‐induced diabetic cardiomyopathy

Abstract

Inflammation plays a critical role in the development of diabetic cardiomyopathy (DCM), which has been identified as a major predisposing factor for heart failure in diabetic patients. Previous studies indicated that ivabradine (a specific agent for heart rate [HR] reduction) has anti-inflammatory properties, but its role in DCM remains unknown. This study investigated whether ivabradine exerts a therapeutic effect in DCM. C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ) to induce diabetes; then administered with ivabradine or saline (control). After 12 weeks, the surviving mice were analyzed to determine the cardioprotective effect of ivabradine against DCM. Although treatment with ivabradine did not affect blood glucose levels, it attenuated tumor necrosis factor-α, interleukin-1β, and interleukin-6 messenger RNA (mRNA) expression, inhibited c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) activation, reduced histological abnormalities, myocardial apoptosis and collagen deposition, and improved cardiac function in the diabetic mice. Interestingly, the anti-inflammatory and antiapoptotic properties of ivabradine, but not its inhibitory effect on JNK and p38 MAPK, were observed in high-glucose-cultured neonatal rat ventricular cardiomyocytes. Attenuating inflammation and apoptosis via intramyocardial injection of lentiviruses carrying short hairpin RNA targeting JNK and p38 MAPK validated that the anti-inflammatory and antiapoptotic effects of ivabradine were partly attributed to JNK and p38 MAPK inactivation in diabetic mice. In summary, these data indicate that ivabradine-mediated improvement of cardiac function in STZ-induced diabetic mice may be partly attributed to inhibition of JNK/p38 MAPK-mediated inflammation and apoptosis, which is dependent on the reduction in HR.

Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR‐141‐mediated NLRP3 inflammasome and TGF‐β1/Smads signaling in diabetic cardiomyopathy

“…The markers of inflammation are often elevated in patients suffering from DCM, and inhibition of the inflammatory signaling pathways reduces insulin resistance and improves hyperglycemia in animal models of DM. 27,28 It has been documented that inflammation plays a critical role in the pathogenesis of DCM, which leads to cardiac fibrosis by promoting collagen deposition. In the past decade, NLRP3 inflammasome, one of the most widely studied inflammasomes, is considered a potential therapeutic target for various inflammatory diseases, including DCM.…”

Lycium barbarum polysaccharide attenuates cardiac hypertrophy, inhibits calpain‑1 expression and inhibits NF‑κB activation in streptozotocin‑induced diabetic rats

“…In addition, a previous study has revealed that the inhibition of the reactive oxygen species (ROS)-/NF-κB pathway protects cardiomyocytes from hypertrophy (10). There has been increasing evidence that inflammation and adhesion molecules are involved in diabetes and the progression of cardiac hypertrophy in diabetes (11,12). NF-κB serves an important role in the regulation of pro-inflammatory genes leading to the overproduction of inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) in the hearts of isoproterenol treated rats (13).…”

Requisite roles of LOX-1, JNK, and arginase in diabetes-induced endothelial vasodilator dysfunction of porcine coronary arterioles

“…Cardiac dysfunction in type 1 diabetes is associated with local inflammation in the heart, including activation of stress-activated kinases JNK and p38 [56]. It is important to address the potential contribution of these kinases to coronary arteriolar vasomotor dysfunction during diabetes because p38 [46] and JNK [31] have been shown to mediate coronary arteriolar dysfunction elicited by the inflammatory molecules CRP and tumor necrosis factor-α, respectively.…”