Fibrotic Signaling in Cardiac Fibroblasts and Vascular Smooth Muscle Cells: The Dual Roles of Fibrosis in HFpEF and CAD

Abstract

Patients with heart failure with preserved ejection fraction (HFpEF) and atherosclerosis-driven coronary artery disease (CAD) will have ongoing fibrotic remodeling both in the myocardium and in atherosclerotic plaques. However, the functional consequences of fibrosis differ for each location. Thus, cardiac fibrosis leads to myocardial stiffening, thereby compromising cardiac function, while fibrotic remodeling stabilizes the atherosclerotic plaque, thereby reducing the risk of plaque rupture. Although there are currently no drugs targeting cardiac fibrosis, it is a field under intense investigation, and future drugs must take these considerations into account. To explore similarities and differences of fibrotic remodeling at these two locations of the heart, we review the signaling pathways that are activated in the main extracellular matrix (ECM)-producing cells, namely human cardiac fibroblasts (CFs) and vascular smooth muscle cells (VSMCs). Although these signaling pathways are highly overlapping and context-dependent, effects on ECM remodeling mainly act through two core signaling cascades: TGF-β and Angiotensin II. We complete this by summarizing the knowledge gained from clinical trials targeting these two central fibrotic pathways.

Losartan Reduces Remodeling and Apoptosis in an Adriamycin-Induced Cardiomyopathy Rat Model

“…In this system, Ang-II acts as a potent growth factor and cytokine in the heart, exerting effects on vascular smooth muscle cells, cardiac muscle cells, and cardiac fibroblasts. This is achieved through its interaction with the AT1R [ 2 - 4 ].…”

“…In the pathogenesis of ADR-induced cardiomyopathy, angiotensin II (Ang-II) of the renin-angiotensin system (RAS) intervenes with the angiotensin type I receptor (AT1R) and activates intracellular signaling cascades. These cascades induce deleterious effects by generating reactive oxygen species (ROS), promoting fibrosis, and causing myocardial apoptosis [ 2 - 4 ]. As noted in previous studies, Ang-II plays a key role in the process of anthracycline- induced cardiotoxicity [ 5 , 6 ].…”

Associations of cartilage intermediate layer protein 1 and hypoxia-inducible factor-1-alpha with transthoracic echocardiography results in patients with heart failure with preserved ejection fraction

“…Обсуждение В рамках настоящей работы был проведен сравнительный анализ клинико-анамнестических, лабораторных и инструментальных показателей у пациентов с СНсФВ с целью определить ассоциации уровней CILP-1 и HIF-1α и показателей трансторакальной ЭхоК Г. Так, у пациентов с СНсФВ вне зависимости от ИМТ отмечена отрицательная корреляционная связь концентрации в крови CILP-1 с иКСО ЛП, который является "большим" морфологическим критерием СНсФВ согласно алгоритму HFA-PEFF (Heart Failure Association -P: Pre-test assessment, E: Echocardiography and Natriuretic Peptide Score, F1: Functional testing, F2: Final aetiology) [16]. Известно, что фиброз миокарда является ключевым звеном патогенеза диастолической дисфункции и СНсФВ [17], однако в представленную выборку вошли пациенты с I-II функциональным классом СНсФВ и относительно небольшим увеличением объема ЛП, что дает основания предполагать низкую степень фиброза ЛП в исследуемой группе [18].…”

The heterocellular heart: identities, interactions, and implications for cardiology

“…Substantial plasticity of smooth muscle cells has been observed, including conversion to myofibroblast- or macrophage-like phenotypes [ 184 ]. Although smooth muscle cells are not thought to give rise to fibroblasts in the healthy heart [ 84 ], they modulate ECM remodelling by paracrine signalling [ 13 , 150 ].…”