Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases

Cardiovascular remodeling occurs in cardiomyocytes, collagen meshes, and vascular beds in the progress of cardiac insufficiency caused by a variety of cardiac diseases such as chronic ischemic heart disease, chronic overload heart disease, myocarditis, and myocardial infarction. The morphological changes that occur as a result of remodeling are the critical pathological basis for the occurrence and development of serious diseases and also determine morbidity and mortality. Therefore, the inhibition of remodeling is an important approach to prevent and treat heart failure and other related diseases. The endoplasmic reticulum (ER) and mitochondria are tightly linked by ER-mitochondria contacts (ERMCs). ERMCs play a vital role in different signaling pathways and provide a satisfactory structural platform for the ER and mitochondria to interact and maintain the normal function of cells, mainly by involving various cellular life processes such as lipid metabolism, calcium homeostasis, mitochondrial function, ER stress, and autophagy. Studies have shown that abnormal ERMCs may promote the occurrence and development of remodeling and participate in the formation of a variety of cardiovascular remodeling-associated diseases. This review focuses on the structure and function of the ERMCs, and the potential mechanism of ERMCs involved in cardiovascular remodeling, indicating that ERMCs may be a potential target for new therapeutic strategies against cardiovascular remodeling-induced diseases.

Arterial and Cardiac Remodeling Associated With Extra Weight Gain in an Isolated Abdominal Obesity Cohort

Introduction: This study aims to assess the changes in cardiovascular remodeling attributable to bodyweight gain in a middle-aged abdominal obesity cohort. A remodeling worsening might explain the increase in cardiovascular risk associated with a dynamic of weight gain.Methods: Seventy-five middle-aged subjects (56 ± 5 years, 38 women) with abdominal obesity and no known cardiovascular disease underwent MRI-based examinations at baseline and at a 6.1 ± 1.2-year follow-up to monitor cardiovascular remodeling and hemodynamic variables, most notably the effective arterial elastance (Ea). Ea is a proxy of the arterial load that must be overcome during left ventricular (LV) ejection, with increased EA resulting in concentric LV remodeling.Results: Sixteen obese subjects had significant weight gain (>7%) during follow-up (WG+), whereas the 59 other individuals did not (WG–). WG+ and WG– exhibited significant differences in the baseline to follow-up evolutions of several hemodynamic parameters, notably diastolic and mean blood pressures (for mean blood pressure, WG+: +9.3 ± 10.9 mmHg vs. WG–: +1.7 ± 11.8 mmHg, p = 0.022), heart rate (WG+: +0.6 ± 9.4 min−1 vs. −8.9 ± 11.5 min−1, p = 0.003), LV concentric remodeling index (WG: +0.08 ± 0.16 g.mL−1 vs. WG−: −0.02 ± 0.13 g.mL−1, p = 0.018) and Ea (WG+: +0.20 ± 0.28 mL mmHg−1 vs. WG−: +0.01 ± 0.30 mL mmHg−1, p = 0.021). The evolution of the LV concentric remodeling index and Ea were also strongly correlated in the overall obese population (p < 0.001, R2 = 0.31).Conclusions: A weight gain dynamic is accompanied by increases in arterial load and load-related concentric LV remodeling in an isolated abdominal obesity cohort. This remodeling could have a significant impact on cardiovascular risk.

NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond

The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors. Nuclear receptors of the subfamily 4 group A (NR4A) have recently emerged as key master genes in multiple cellular processes and vital functions of different organs, and have been involved in a variety of high-incidence human pathologies including atherosclerosis and other CVDs. This paper reviews the major findings involving NR4A3 (Neuron-derived Orphan Receptor 1, NOR-1) in the cardiovascular remodeling operating in these diseases.

Glycation and Glycosylation in Cardiovascular Remodeling: Focus on Advanced Glycation End Products and O-Linked Glycosylations as Glucose-Related Pathogenetic Factors and Disease Markers

Glycation and glycosylation are non-enzymatic and enzymatic reactions, respectively, of glucose, glucose metabolites, and other reducing sugars with different substrates, such as proteins, lipids, and nucleic acids. Increased availability of glucose is a recognized risk factor for the onset and progression of diabetes-mellitus-associated disorders, among which cardiovascular diseases have a great impact on patient mortality. Both advanced glycation end products, the result of non-enzymatic glycation of substrates, and O-linked-N-Acetylglucosaminylation, a glycosylation reaction that is controlled by O-N-AcetylGlucosamine (GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), have been shown to play a role in cardiovascular remodeling. In this review, we aim (1) to summarize the most recent data regarding the role of glycation and O-linked-N-Acetylglucosaminylation as glucose-related pathogenetic factors and disease markers in cardiovascular remodeling, and (2) to discuss potential common mechanisms linking these pathways to the dysregulation and/or loss of function of different biomolecules involved in this field.

The Role of Uremic Intoxication in the Development of Cardiovascular Remodeling in Patients with Chronic Kidney Disease Stages 3a-5d

In recent decades, the prevalence of chronic kidney disease (CKD) in the population has a clear upward trend. This is due, first of all, to an increase in the frequency of occurrence of the main factors leading to its development: diabetes mellitus and arterial hypertension. The progression of CKD against the background of the action of these factors leads to a steady loss of the kidneys of their filtration capacity and the development of complications associated with this process. These include, first of all, metabolic and acid-base disorders, electrolyte abnormalities, uremic intoxication, overhydration, protein-energy wasting, sarcopenia and others. Most of them are involved in the development of endothelial dysfunction and the formation of cardiovascular remodeling (CVR), as a key component of the cardiorenal continuum. At the same time, there is a mutual negative influence of pathology of the cardiovascular system on renal function and manifestations of CKD on cardiovascular hemodynamics. This “vicious circle” leads to the development of end-stage renal disease and an increase in cardiovascular risk and mortality from diseases of the circulatory system in patients with advanced stages of CKD. In this connection, this work is devoted to the study of the role of uremic intoxication and, in particular, indoxyl sulfate, in the development of CVR in patients with CKD at different stages of the disease.

Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II - induced cardiac hypertrophy and vascular remodeling

Background: Cardiovascular complications are the leading cause of death and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from Ang II-induced end organ damage. Methods and Results: Angiotensin II (ANGII) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (TG) and wild type (WT) littermates for two or four weeks. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure (SBP) was measured weekly and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after one week of ANGII infusion was not different between the groups, while TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 weeks of ANGII infusion in the high dose and after 4 weeks in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross sectional area and less interstitial fibrosis as compared to WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2 and showed better endothelium-dependent relaxation. Conclusions: We demonstrated that overexpression of DDAH1 protects from ANGII-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.

Abstract P252: Smooth Muscle At1a Receptor Mediates Perivascular Fibrosis In Angiotensin Ii-infused Mice

Angiotensin II (Ang II) signaling via AT1 receptor has been shown to play a critical role in the pathogenesis of hypertension, cardiovascular hypertrophy and fibrosis. We have demonstrated that ADAM17 expressed in vascular smooth muscle cells (VSMC) mediates EGF receptor activation and promotes cardiac hypertrophy and perivascular fibrosis induced by Ang II. It is conceivable that Ang II signaling in VSMCs specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. In a recent study, deficiency of smooth muscle AT1a receptors results in diminished hypertension and protection from cardiac hypertrophy induced by Ang II. However, we have limited understanding whether smooth muscle AT1a receptors affects hypertensive fibrosis in vasculature. Thus, this study was designed to elucidate the roles of the AT1a receptor in VSMCs in cardiovascular remodeling including fibrosis during Ang II stimulation using VSMC AT1a receptor deficient mice. To delete the AT1a receptor from VSMCs, we crossed C57BL/6 transgenic mouse lines expressing Cre recombinase under the control of the sm22α promoter (KIsm22α-Cre). Male AT1a flox/flox KIsm22α-Cre+/- (SMKO) and Controls (AT1a flox/flox KIsm22α-Cre-/-) mice were infused with Ang II (1 μg/kg/min) for 2 weeks via osmotic mini-pump. In Control mice, Ang II infusion for 2 weeks induced cardiac hypertrophy indicated by heart-to-body weight ratio and echocardiogram. After 2 weeks of Ang II infusion, heart-to-body weight ratios were significantly increased in Control mice compared with AT1a SMKO mice (6.04 versus 4.89, respectively, p=0.032). Cardiac wall hypertrophy was seen in Controls after 2 weeks of Ang II infusion, which was attenuated in AT1a SMKOs. Control mice (n=5) showed vascular medial hypertrophy and perivascular fibrosis, whereas these phenotypic changes were attenuated in SMKO mice (n=4). In conclusion, AT1a receptors from VSMC could mediate Ang II-induced cardiovascular hypertrophy and perivascular fibrosis. Whether the data can be fully explained by the prevention of hypertension remains to be determined, the data contrast to the past manuscript showing a protective effect in AT1a flox/flox S100A4-Cre+/- mice (fibroblast silencing) with Ang II infusion.