N-acetylcysteine with low-dose estrogen reduces cardiac ischemia-reperfusion injury

Abstract

Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.

N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function

“…This may help promote clinical usage of NAC. Apart from NAFLD, NAC was also reported to be effective in treating obesity ( Shen et al, 2018 ), ischemia-reperfusion injury of cardiomyocyte ( Sivasinprasasn et al, 2019 ), and muscle atrophy ( Wang et al, 2014b ). Taken together, these reports, along with our data, indicate that NAC can be a useful agent to treat mitochondria dysfunction-related diseases.…”

Sex-Related Effects on Cardiac Development and Disease

“…In this context, several pre-clinical data support the notion that E2 facilitates endogenous cardiac repair processes in animal models of ischemia/reperfusion (I/R) and myocardial infarction (MI) [ 101 , 123 ]. Importantly, ovariectomized (OVX) animals demonstrate decreased post-ischemic functional recovery and increased mitochondrial and cardiomyocyte damage, whereas E2 treatment reverses these effects [ 13 , 124 , 125 ]. The underlying molecular mechanisms are both genomic and non-genomic [ 101 , 102 , 123 ] and include modulation of ion channel activity [ 104 , 124 , 126 ], antioxidant effects [ 101 , 127 , 128 ], anti-inflammatory or anti-apoptotic effects [ 129 , 130 , 131 ], and effects on endothelial cells [ 132 , 133 ].…”

“…Importantly, ovariectomized (OVX) animals demonstrate decreased post-ischemic functional recovery and increased mitochondrial and cardiomyocyte damage, whereas E2 treatment reverses these effects [ 13 , 124 , 125 ]. The underlying molecular mechanisms are both genomic and non-genomic [ 101 , 102 , 123 ] and include modulation of ion channel activity [ 104 , 124 , 126 ], antioxidant effects [ 101 , 127 , 128 ], anti-inflammatory or anti-apoptotic effects [ 129 , 130 , 131 ], and effects on endothelial cells [ 132 , 133 ]. Importantly, a significant number of E2-mediated effects involve alterations in PI3K signaling [ 134 , 135 , 136 ].…”

Role of β-Adrenergic Receptors and Estrogen in Cardiac Repair after Myocardial Infarction: An Overview

“…However, long-term treatment with E2 normalizes ventricular wall tension and chamber dimension in MI survivors, promoting increased survival [56]. Furthermore, OVX rats subjected to ischemia-reperfusion (I/R) present significantly decreased post-ischemic recovery of left ventricular function and increased MI extension, and these deleterious effects were avoided by E2 replacement [57]. In OVX-MI mice, activation of ERα reduces mortality in spite of increasing infarction extension, while stimulation of ERβ accounts for reduced infarction area and increased cardiac hypertrophy and mortality [58].…”

“…present significantly decreased post-ischemic recovery of left ventricular function and in-creased MI extension, and these deleterious effects were avoided by E2 replacement [57]. In OVX-MI mice, activation of ERα reduces mortality in spite of increasing infarction extension, while stimulation of ERβ accounts for reduced infarction area and increased cardiac hypertrophy and mortality [58].…”