Nicotinamide Riboside Supplementation Restores Myocardial Nicotinamide Adenine Dinucleotide Levels, Improves Survival, and Promotes Protective Environment Post Myocardial Infarction.

AIMS: Myocardial infarction (MI) is a major cause of death. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme in oxidative phosphorylation and substrate of sirtuins and poly-ADP ribose polymerases, enzymes critical for cardiac remodeling post-MI. Decreased NAD+ is reported in several heart failure models with paradoxically an upregulation of nicotinamide riboside kinase 2, which uses nicotinamide riboside (NR) as substrate in an NAD+ biosynthetic pathway. We hypothesized that stimulating nicotinamide riboside kinase 2 pathway by NR supplementation exerts cardioprotective effects. METHODS AND RESULTS: MI was induced by LAD ligation in 2-3-month-old male mice. NR was administered daily (1 µmole/g body weight) over 7 days. RT-PCR showed a 60-fold increase in nicotinamide riboside kinase 2 expression 4 days post-MI with a 60% drop in myocardial NAD+ and overall survival of 61%. NR restored NAD+ levels and improved survival to 92%. Assessment of respiration in cardiac fibers revealed mitochondrial dysfunction post-MI, and NR improved complexes II and IV activities and citrate synthase activity, a measure of mitochondrial content. Additionally, NR reduced elevated PARP1 levels and activated a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. CONCLUSION: Our data show that nicotinamide riboside could be useful for MI management.

Sexual dimorphism in acute myocardial infarction-induced acute kidney injury: cardiorenal deteriorating effects of ovariectomy in premenopausal female mice.

Acute kidney injury (AKI) is a common complication of cardiovascular diseases (CVDs) in both males and females, increasing mortality rate substantially. Premenopausal females appear to be more protected, suggesting a potential protective role of female sex hormones. Here, we tested the hypothesis that ovariectomy (OVX) eliminates the beneficial effect of female sex on renal protection following acute myocardial infarction (MI). Seven days post-MI, both sexes exhibited worsened kidney function and a substantial decrease in total kidney NAD levels. Unlike MI female mice, MI males showed exacerbated morphological alterations with increased proinflammatory, proapoptotic, and profibrotic biomarkers. The expression of NAD+ biosynthetic enzymes NAMPT and NMRK-1 was increased in MI females only, while males showed a substantial increase in NAD+ consuming enzyme PARP-1. OVX did not eliminate the female-sex protection of glomerular morphology but was associated with swelling of proximal convoluted tubules with MI as in males. With OVX, MI females had enhanced proinflammatory cytokine release, and a further decrease in creatinine clearance and urine output was observed. Our findings suggest that MI induced AKI in both sexes with pre-menopausal female mice being more protected. Ovariectomy worsens aspects of AKI in females after MI, which may portend increased risk for development of chronic kidney disease.

Sex differences in cardiac remodeling post myocardial infarction with acute cigarette smoking.

BACKGROUND: Whether cigarette smoking affects the heart post-myocardial infarction (MI) in a sex-dependent way remains controversial. Using a mouse model, we investigated cardiac remodeling under the influence of acute cigarette smoke (CS) exposure following ischemic injury in both sexes. METHODS: Ten cigarettes were smoked twice daily for 2 weeks followed by MI and then 1 additional week post permanent LAD ligation. Cardiac function, histology, and infarct size were assessed, and inflammatory markers quantified by RT-PCR. Statistical comparisons were performed using an unpaired t test or ANOVA followed by Tukey post hoc test. RESULTS: We observed that cigarette smoking exacerbated both left and right ventricular remodeling only in males at an early stage of post-MI. Females did not display a significant structural and/or functional alteration within 7 days of cardiac remodeling post-MI upon CS exposure. Worsened right ventricular remodeling in males was independent of pulmonary congestion. CS-exposed males exhibited enhanced increases in left ventricular end systolic and diastolic volumes, as well as reductions in ejection fraction and fractional area changes of left ventricular base. At day 7, infarct size was increased by cigarette smoking in males only, which was accompanied by enhanced collagen deposition in both the infarcted and peri-infarcted areas. Both IL-6 and TNF-α mRNA expression significantly increased in CS-exposed MI male group only at day 7 post-MI suggestive of prolonged inflammation. CONCLUSIONS: These findings indicate that CS exposure worsens the progression of cardiac remodeling post-MI in male sex in a significant manner compared to female sex at least at early stages.

Sex-based differences in myocardial infarction-induced kidney damage following cigarette smoking exposure: more renal protection in premenopausal female mice.

The impact of cigarette smoking (CS) on kidney homeostasis in the presence of myocardial infarction (MI) in both males and females remains poorly elucidated. C57BL6/J mice were exposed to 2 weeks of CS prior to MI induction followed by 1 week of CS exposure in order to investigate the impact of CS on kidney damage in the presence of MI. Cardiac hemodynamic analysis revealed a significant decrease in ejection fraction (EF) in CS-exposed MI male mice when compared with the relative female subjects, whereas cardiac output (CO) comparably decreased in CS-exposed MI mice of both sexes. Kidney structural alterations, including glomerular retraction, proximal convoluted tubule (PCT) cross-sectional area, and total renal fibrosis were more pronounced in CS-exposed MI male mice when compared with the relative female group. Although renal reactive oxygen species (ROS) generation and glomerular DNA fragmentation significantly increased to the same extent in CS-exposed MI mice of both sexes, alpha-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) significantly increased in CS-exposed MI male mice, only. Metabolically, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside-1 (NMRK-1) substantially increased in CS-exposed MI female mice only, whereas sirtuin (SIRT)-1 and SIRT-3 substantially decreased in CS-exposed MI male mice compared with their relative female group. Additionally, renal NAD levels significantly decreased only in CS-exposed MI male mice. In conclusion, MI female mice exhibited pronounced renal protection following CS when compared with the relative male groups.

IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.

Gender-biased kidney damage in mice following exposure to tobacco cigarette smoke: More protection in premenopausal females.

Multiple clinical studies documented renal damage in chronic cigarette smokers (CS) irrespective of their age and gender. Premenopausal female smokers are known to exert a certain cardiovascular and renal protection with undefined mechanisms. Given the multiple demographic variables within clinical studies, this experimental study was designed to be the first to assess whether gender-biased CS-induced kidney damage truly exists between premenopausal female and age-matched C57Bl6J male mice when compared to their relative control groups. Following 6 weeks of CS exposure, cardiac function, inflammatory marker production, fibrosis formation, total and glomerular ROS levels, and glomerulotubular homeostasis were assessed in both genders. Although both CS-exposed male and female mice exhibited comparable ROS fold change relative to their respective control groups, CS-exposed male mice showed a more pronounced fibrotic deposition, inflammation, and glomerulotubular damage profile. However, the protection observed in CS-exposed female group was not absolute. CS-exposed female mice exhibited a significant increase in fibrosis, ROS production, and glomerulotubular alteration but with a pronounced anti-inflammatory profile when compared to their relative control groups. Although both CS-exposed genders presented with altered glomerulotubular homeostasis, the alteration phenotype between genders was different. CS-exposed males showed a significant decrease in Bowman's space along with reduced tubular diameter consistent with an endocrinization pattern of chronic tubular atrophy, suggestive of an advanced stage of glomerulotubular damage. CS-exposed female group, on the other hand, displayed glomerular hypertrophy with a mild tubular dilatation profile suggestive of an early stage of glomerulotubular damage that generally precedes collapse. In conclusion, both genders are prone to CS-induced kidney damage with pronounced female protection due to a milder damage slope.

Cerebral blood flow alteration following acute myocardial infarction in mice.

Heart failure is associated with low cardiac output (CO) and low brain perfusion that imposes a significant risk for accelerated brain ageing and Alzheimer's disease (AD) development. Although clinical heart failure can emerge several years following acute myocardial infarction (AMI), the impact of AMI on cerebral blood flow (CBF) at early stages and up to 30 days following MI is unknown. Sixteen months old male mice underwent left anterior descending (LAD) coronary artery ligation. Hemodynamics analyses were performed at baseline and at days 1, 7, and 30 post-MI. Left ventricular (LV) ejection fraction (EF), LV volumes, CO, and right common carotid artery (RCCA) diameter were recorded by echocardiography. RCCA flow (RCCA FL) was measured by Doppler echocardiography. LV volumes consistently increased (P<0.0012) and LV systolic function progressively deteriorated (P<0.0001) post-MI. CO and RCCA FL showed a moderate but significant decrease over the course of MI with similar fluctuation pattern such that both variables were decreased at day 1, increased at day 7, and decreased at 30 days post-MI. Correlation and regression analyses between CO and RCCA FL showed a strong correlation with significance at baseline and day 30 post-MI (R = 0.71, P=0.03, and R = 0.72, P=0.03, respectively). Days 1 and 7 analyses between CO and RCCA FL showed moderate correlation with non-significance post-MI (R = 0.51, P=0.2, and R = 0.56, P=0.12, respectively). In summary, CBF significantly decreased following AMI and remained significantly decreased for up to 30 days, suggesting a potential risk for brain damage that could contribute to cognitive dysfunction later in life.

Conflicting vascular and metabolic impact of the IL-33/sST2 axis.

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases.

Cardiac Autonomic Neuropathy as a Result of Mild Hypercaloric Challenge in Absence of Signs of Diabetes: Modulation by Antidiabetic Drugs.

Cardiac autonomic neuropathy (CAN) is an early cardiovascular complication of diabetes occurring before metabolic derangement is evident. The cause of CAN remains elusive and cannot be directly linked to hyperglycemia. Recent clinical data report cardioprotective effects of some antidiabetic drugs independent of their hypoglycemic action. Here, we used a rat model receiving limited daily increase in calories from fat (HC diet) to assess whether mild metabolic challenge led to CAN in absence of interfering effects of hyperglycemia, glucose intolerance, or obesity. Rats receiving HC diet for 12 weeks showed reduction in baroreceptor sensitivity and heart rate variability despite lack of change in baseline hemodynamic and cardiovascular structural parameters. Impairment of cardiac autonomic control was accompanied with perivascular adipose inflammation observed as an increased inflammatory cytokine expression, together with increased cardiac oxidative stress, and signaling derangement characteristic of diabetic cardiomyopathy. Two-week treatment with metformin or pioglitazone rectified the autonomic derangement and corrected the molecular changes. Switching rats to normal chow but not to isocaloric amounts of HC for two weeks reversed CAN. As such, we conclude that adipose inflammation due to increased fat intake might underlie development of CAN and, hence, the beneficial effects of metformin and pioglitazone.

Acute Exposure to Cigarette Smoking Followed by Myocardial Infarction Aggravates Renal Damage in an In Vivo Mouse Model.

Cigarette smoking (S) is a risk factor for progressive chronic kidney disease, renal dysfunction, and renal failure. In this study, the effect of smoking on kidney function was investigated in a mouse model of myocardial infarction (MI) using 4 groups: control (C), smoking (S), MI, and S+MI. Histological analysis of S+MI group showed alterations in kidney structure including swelling of the proximal convoluted tubules (PCTs), thinning of the epithelial lining, focal loss of the brush border of PCTs, and patchy glomerular retraction. Molecular analysis revealed that nephrin expression was significantly reduced in the S+MI group, whereas sodium-hydrogen exchanger-1 (NHE-1) was significantly increased, suggesting altered glomerular filtration and kidney functions. Moreover, S+MI group, but not S alone, showed a significant increase in the expression of connective tissue growth factor (CTGF) and fibrotic proteins fibronectin (FN) and α-smooth muscle actin (SMA), in comparison to controls, in addition to a significant increase in mRNA levels of IL-6 and TNF-α inflammatory markers. Finally, reactive oxygen species (ROS) production was significantly accentuated in S+MI group concomitant with a significant increase in NOX-4 protein levels. In conclusion, smoking aggravates murine acute renal damage caused by MI at the structural and molecular levels by exacerbating renal dysfunction.

Functional, Cellular, and Molecular Remodeling of the Heart under Influence of Oxidative Cigarette Tobacco Smoke.

Passive and active chronic cigarette smoking (CS) remains an international epidemic and a key risk factor for cardiovascular disease (CVD) development. CS-induced cardiac damage is divided into two major and interchangeable mechanisms: (1) direct adverse effects on the myocardium causing smoking cardiomyopathy and (2) indirect effects on the myocardium by fueling comorbidities such as atherosclerotic syndromes and hypertension that eventually damage and remodel the heart. To date, our understanding of cardiac remodeling following acute and chronic smoking exposure is not well elucidated. This manuscript presents for the first time the RIMD (oxidative stress (R), inflammation (I), metabolic impairment (M), and cell death (D)) detrimental cycle concept as a major player in CS-induced CVD risks and direct cardiac injury. Breakthroughs and latest findings in the field with respect to structural, functional, cellular, and molecular cardiac remodeling following chronic smoking exposure are summarized. This review also touches the genetics/epigenetics of smoking as well as the smoker's paradox and highlights the most currently prominent pharmacological venues to mitigate CS-induced adverse cardiac remodeling.