Vitamin C Regulates the Profibrotic Activity of Fibroblasts in In Vitro Replica Settings of Myocardial Infarction

Abstract

Extracellular collagen remodeling is one of the central mechanisms responsible for the structural and compositional coherence of myocardium in patients undergoing myocardial infarction (MI). Activated primary cardiac fibroblasts following myocardial infarction are extensively investigated to establish anti-fibrotic therapies to improve left ventricular remodeling. To systematically assess vitamin C functions as a potential modulator involved in collagen fibrillogenesis in an in vitro model mimicking heart tissue healing after MI. Mouse primary cardiac fibroblasts were isolated from wild-type C57BL/6 mice and cultured under normal and profibrotic (hypoxic + transforming growth factor beta 1) conditions on freshly prepared coatings mimicking extracellular matrix (ECM) remodeling during healing after an MI. At 10 μg/mL, vitamin C reprogramed the respiratory mitochondrial metabolism, which is effectively associated with a more increased accumulation of intracellular reactive oxygen species (iROS) than the number of those generated by mitochondrial reactive oxygen species (mROS). The mRNA/protein expression of subtypes I, III collagen, and fibroblasts differentiations markers were upregulated over time, particularly in the presence of vitamin C. The collagen substrate potentiated the modulator role of vitamin C in reinforcing the structure of types I and III collagen synthesis by reducing collagen V expression in a timely manner, which is important in the initiation of fibrillogenesis. Altogether, our study evidenced the synergistic function of vitamin C at an optimum dose on maintaining the equilibrium functionality of radical scavenger and gene transcription, which are important in the initial phases after healing after an MI, while modulating the synthesis of de novo collagen fibrils, which is important in the final stage of tissue healing.

Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction

“…At specific concentration levels, ROS has a detrimental or beneficial role in cell function (levels see Section 3.1 ) [ 79 ]. Oxidative stress is one of the main contributors to generating uncontrollably large amounts of ROS.…”

“…Although the mechanisms for reducing the cardiovascular risk remain unclear, the role of vitamin C in scavenging ROS [ 178 ], enhancing NO production [ 179 ], and its potential benefits for microperfusion [ 177 ], myocardial protection [ 79 ], and hemodynamic stability [ 180 ]—especially in critically ill patients [ 181 ]—is increasingly recognized.…”

Vegetable and Fruit Intake Variety and Cardiovascular Health and Mortality: A Systematic Review and Meta-Analysis of Observational Studies

“…For example, in vitro evidence has shown that vitamin C, such as from citrus fruits and bell peppers, can increase nitric oxide bioavailability, which can induce vasodilation and promote the integrity of the endothelium and hence lower blood pressure [49]. Vitamin C may also protect cell constituents against oxidative stress and aid in the synthesis of several relevant biomolecules via acting as an enzymatic cofactor, thus playing a pivotal role in several processes involved in the pathogenesis of CVD [50,51]. These antioxidant properties are notable as reducing oxidative stress is believed to be a key factor in the prevention of cardiovascular pathology [52].…”

From Cardiovascular Prevention and Differential Diagnosis to the Treatment of Myocardial Damage—Experimental and Human Perspectives

“…In an elegant experimental study, Yichen Xu et al [5] focused on the topic of connective tissue changes after myocardial infarction, similar to the study by Schumacher et al [4]; however, they went further and investigated the effect of vitamin C at various doses in a mice model. Concentrations from 0 to 50 ug/mL (0, 10, 20, 30, 40, 50 ug/mL) were used.…”