Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and is widespread in US population and worldwide. Despite of the heterogeneous and distinct features of DCM, the clinical relevance of DCM is now becoming established. DCM progresses to pathological cardiac remodeling with the higher risk of heart attack and subsequent heart failure in diabetic patients. In this review, we emphasize lipid substrate quality and the phenotypic, metabolic, and biochemical stressors of DCM in the rodent and human pathophysiology. We discuss lipoxygenase signaling in the inflammatory pathway with multiple contributing and confounding factors leading to DCM. Additionally, emerging biochemical pathways are emphasized to make progress toward therapeutic advancement to treat DCM

Role of Neutrophils in Ischemic Heart Failure

Amplified innate leukocytes (neutrophils and monocytes/macrophages) are associated with advanced ischemic and non-ischemic heart failure (HF). Intensified neutrophilic leukocytosis (neutrophilia) and sustained activation of neutrophils is the predominant factor that determines over activated inflammation in acute HF and the outcome of long-term chronic HF. After heart attack, the first wave of innate responsive and short-lived neutrophils is essential for the initiation of inflammation, resolution of inflammation, and cardiac repair, however uncontrolled and long-term activation of neutrophils leads to collateral damage of myocardium. In the presented review, we highlighted the interactive and integrative role of neutrophil phenotypes in cellular and molecular events of ischemic HF. In addition, we discussed the current, nonimmune, immune, and novel paradigms of neutrophils in HF associated with differential factors with a specific interest in non-resolving inflammation and resolution physiology

Obesity and Cardiometabolic Defects in Heart Failure Pathology

Obesity is a major global epidemic that sets the stage for diverse multiple pathologies, including cardiovascular disease. The obesity-related low-grade chronic inflamed milieu is more pronounced in aging and responsive to cardiac dysfunction in heart failure pathology. Metabolic dysregulation of obesity integrates with immune reservoir in spleen and kidney network. Therefore, an integrative systems biology approach is necessary to delay progressive cardiac alternations. The purpose of this comprehensive review is to largely discuss the impact of obesity on the cardiovascular pathobiology in the context of problems and challenges, with major emphasis on the diversified models, and to study cardiac remodeling in obesity. The information in this article is immensely helpful in teaching advanced undergraduate, graduate, and medical students about the advancement and impact of obesity on cardiovascular health

Immune Responsive Resolvin D1 Programs Peritoneal Macrophages and Cardiac Fibroblast Phenotypes in Diversified Metabolic Microenvironment

Bioactive lipid mediators derived from n-3 and n-6 fatty acids are known to modulate leukocytes. Metabolic transformation of essential fatty acids to endogenous bioactive molecules plays a major role in human health. Here we tested the potential of substrates; linoleic acid (LA) and docosahexaenoic acid (DHA) and their bioactive products; resolvin D1 (RvD1) and 12- S-hydroxyeicosatetraenoic acids (HETE) to modulate macrophage plasticity and cardiac fibroblast phenotype in presence or absence of lipid metabolizing enzyme 12/15-lipoxygenase (LOX). Peritoneal macrophages and cardiac fibroblasts were isolated from wild-type (C57BL/6J) and 12/15LOX −/− mice and treated with DHA, LA, 12(S)-HETE, and RvD1 for 4, 8, 12, and 24 hr. LA, DHA, 12(S)-HETE, and RvD1 elicited mRNA expression of proinflammatory markers; tumor necrosis factor-α (Tnf-α), interleukin 6 (IL-6), chemokine (C–C motif) ligand 2 (Ccl2), and IL-1β in wild type (WT) and in 12/15LOX −/− macrophages at early time point (4 hr). Bioactive immunoresolvent RvD1 lowered the levels of Tnf-α, IL-6, and IL-1β at 24 hr time point. Both DHA and RvD1 stimulated the proresolving markers such as arginase 1 (Arg-1), chitinase-like protein 3 (Ym-1), and mannose receptor C-type 1 in WT macrophage. RvD1 induced proresolving phenotype Arg-1 expression in both WT 12/15LOX −/− macrophages even in presence of 12(S)-HETE. RvD1 peaked 5LOX expression in both WT and 12/15LOX −/− at 24 hr time point compared with DHA. RvD1 diminished cyclooxygenase-2 but upregulated 5LOX expression in fibroblast compared with DHA. In summary, the feed-forward enzymatic interaction with fatty acids substrates and direct mediators (RvD1 and 12(S)-HETE) are responsive in determining macrophages phenotype and cardiac fibroblast plasticity. Particularly, macrophages and fibroblast phenotypes are responsive to milieu and RvD1 governs the milieu-dependent chemokine signaling in presence or absence of 12/15LOX enzyme to resolve inflammation

Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis

Abstract Background Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition. Methods This study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence. Results Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment. Conclusion Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.</p

Immune Responsive Resolvin D1 Programs Myocardial Infarction–Induced Cardiorenal Syndrome in Heart Failure

Resolvins are innate, immune responsive, bioactive mediators generated after myocardial infarction (MI) to resolve inflammation. The MI-induced bidirectional interaction between progressive left ventricle (LV) remodeling and kidney dysfunction is known to advance cardiorenal syndrome (CRS). Whether resolvins limit MI-induced cardiorenal inflammation is unclear. Thus, to define the role of exogenous resolvin D (RvD)-1 in post-MI CRS, we subjected 8- to 12-wk-old male C57BL/6 mice to coronary artery ligation. RvD1 was injected 3 h after MI. MI mice with no treatment served as MI controls (d 1 and 5). Mice with no surgery served as naive controls. In the injected mice, RvD1 promoted neutrophil (CD11b+/Ly6G+) egress from the infarcted LV, compared with the MI control group at d 5, indicative of neutrophil clearance and thereby resolved inflammation. Further, RvD1-injected mice showed higher reparative macrophages (F4/80+/Ly6Clow/CD206+) in the infarcted LV than did MI control mice at d 5 after MI. RvD1 suppressed the miRNA storm at d 1 and limited the MI-induced edematous milieu in a remote area of the LV compared with the MI control at d 5 after MI. Also, RvD1 preserved the nephrin expression that was diffuse in the glomerular membrane at d 5 and 28 in MI controls, indicating renal injury. RvD1 attenuated MI-induced renal inflammation, decreasing neutrophil gelatinase-associated lipocalin and proinflammatory cytokines and chemokines in the kidney compared with the MI control. In summary, RvD1 clears MI-induced inflammation by increasing resolving leukocytes and facilitates renoprotective mechanisms to limit CRS in acute and chronic heart failure

Inflammation Revisited: Inflammation Versus Resolution of Inflammation Following Myocardial Infarction

Myocardial infarction (MI) is the main cause for the progression of the left ventricle towards congestive heart failure. The optimal healing after MI requires timely induction and resolution of inflammation. Primarily, there have been a number of strategies applied to inhibit the post-MI inflammation but approaches that focus on the resolution of inflammation have sparsely been used in the treatment of heart failure. The early attempts to inhibit post-MI inflammation resulted in adverse outcomes that were realized in heart failure trials. We provide here an overview on the cyclooxygenase (COX)- and lipoxygenase (LOX)-derived lipid mediators that are either impairing or resolving the post-MI inflammation. With the evolution of lipidomics there has been emerging novel bioactive-specialized lipid mediators that promise to resolve chronic inflammation rather than promoting inhibition. The current review is focused on post-MI immune cells kinetics and the unexplored array of lipid mediators that are coordinated by COX and LOX. Thus, an emphasis on COX and LOX poses key questions and potential for the development of novel targets in the heart failure treatment strategy. This updated dynamic approach aims to fuse basic pre-clinical discoveries and translational bioactive lipid-based resolvin discoveries that could be potentially used in the clinic for the treatment of heart failure