Calpain inhibition decreases inflammatory protein expression in vessel walls in a model of chronic myocardial ischemia

Abstract

Introduction Emerging data suggests a link between calpain activation and the enhanced inflammatory response of the cardiovascular system. We hypothesize that calpain activation associates with altered inflammatory protein expression in correlation with the pro-inflammatory profile of the myocardium. Our pig hypercholesterolemic model with chronic myocardial ischemia will be treated with calpain inhibitors (CI) to establish their potentials to improve cardiac function. Methods Yorkshire swine, fed a high cholesterol diet (HC) for four weeks, underwent placement of an ameroid constrictor on the left circumflex artery. Three weeks later animals received either: no drug, high cholesterol control group (CON; n= 8); a low dose CI (0.12 mg/kg; LCI, n= 9); or a high dose CI (0.25 mg/kg; HCI, n= 8). The HC and CI were continued for five weeks, after which the pig was euthanized. The left ventricular myocardial tissue (ischemic and non-ischemic) was harvested and analyzed for inflammatory proteins expression. Data was statistically analyzed via the Kruskal-Wallis and Dunn’s post hoc test. Results CI treatment coincides with increased expression of IKB-α and decreased expression of macrophages, NFkB, IL-1 and TNF-α in the ischemic myocardial tissue as compared to the control group. NFkB array revealed decreased expression of IRF5, JNK1/2, JNK2, CD18, NFkB p65, c-Rel, Sharpin, TNF R1, TNF R2 and DR5 in the ischemic myocardium of the HCI treated group compared to the control. Conclusions Calpain activation in metabolic syndrome is a potential contributor to cardiac dysfunction in metabolic disorders with ischemic background. We suggest calpain inhibition down regulates NFkB signaling in the vessel walls which might be useful for improving myocardial blood flow in ischemic conditions.

Photoreceptor Cell Calcium Dysregulation and Calpain Activation Promote Pathogenic Photoreceptor Oxidative Stress and Inflammation in Prodromal Diabetic Retinopathy

“…Additionally, calpain activation targets proteins in mitochondria that compromise mitochondrial function, resulting in excessive ROS generation and oxidative stress. 18,82,83 This study showed that a CI or capn1 deletion inhibit diabetes-induced increases in the expression of iNOS and ICAM-1 in the retina. Expression of both proteins is regulated by NF-kB, subsequent to degradation of IkBa, and translocation of NF-kB to nucleus.…”

Study on the Active Constituents and Molecular Mechanism of Zhishi Xiebai Guizhi Decoction in the Treatment of CHD Based on UPLC-UESI-Q Exactive Focus, Gene Expression Profiling, Network Pharmacology, and Experimental Validation

“…NFKB, IL1B, TNF, TLR4, and ICAM1 as inflammatory markers play important roles in inflammatory signaling by aiding the activation of NFKB. Moreover, almost all studies on ischemia-associated heart injury demonstrated that the inhibition of NF-kappa B activity could attenuate inflammation-associated injury and improve cardiac function . In this present study, a model of cardiomyocyte hypoxia/reoxygenation pathology was first constructed.…”

“…Moreover, almost all studies on ischemia-associated heart injury demonstrated that the inhibition of NF-kappa B activity could attenuate inflammation-associated injury and improve cardiac function. 54 In this present study, a model of cardiomyocyte hypoxia/reoxygenation pathology was first constructed. qRT-PCR detection analysis concluded that NFKB, IL1B, TNF, TLR4, and ICAM1 were significantly upregulated in the model group, which further suggested that the cardiomyocyte injury model was highly activated.…”

One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration

“…Two Yorkshire swine (male and female; Tufts University, Medford, MA, USA), aged 8 to 10 weeks and weighing between 22 and 25 kg at the time of the initial procedure, were used. This pilot study was designed to assess technical feasibility using an established model of chronic myocardial ischemia developed by Dr. Sellke as previously described [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. To induce chronic ischemia, a small left thoracotomy was performed, the pericardium was opened, and an ameroid constrictor composed of hygroscopic casein material cased in titanium (Research Instruments SW, Escondido, CA, USA) was sized and placed around the proximal left circumflex (LCX) coronary artery (Figure 2B).…”