Cardiac fibrosis is a pathological condition characterized by excessive accumulation of extracellular matrix components within the myocardium, which can lead to impaired cardiac function and heart failure. Studies have shown that lymphocytes including B- and T-cells play important roles in the development and progression of cardiac fibrosis after a myocardial infarction. In this review, we focus on the regulation of cardiac fibrosis by lymphocyte subsets, with a particular emphasis on CD4+ and CD8+ T-cells and their effects on fibroblasts and cardiac remodeling. We also highlight areas for further exploration of the interactions between T-cells and fibroblasts necessary for understanding and treating cardiac fibrosis and heart failure.
Post-myocardial infarction (MI) left ventricular scar formation and composition is one critical determinant of myocardial remodeling. CD8+ T-cells are adverse regulators of the post-MI remodeling process, leading to decreased cardiac function and survival. Based on our previous studies, we hypothesize that CD8+ T-cells impair cardiac function by altering scar composition, leading to poor tissue biomechanical properties.MI was induced by permanently ligating the left anterior descending coronary artery on C57BL6/J wildtype (WT; 3-7 months of age, n≥4/sex/Day post-MI) and CD8atm1mak (CD8-/-; 3-7 months of age, n≥4/sex/Day post-MI) mice. To test potential effects on the scar, CD8-/- mice were injected with either vehicle or naïve splenic CD8+ T-cells via tail vein, 4 hours post-coronary artery ligation. At day 7 post-MI, infarct tissue was collected and underwent passive stretch biomechanical analysis using an Aurora Scientific tension-length dual mode lever servosystem. To examine a possible mechanism of scar alteration, we tested the effects of recombinant granzymes (Gzm) B and K, which are highly expressed in CD8+ T-cells, on collagen cleavage using a fluorogenic collagen cleavage assay.Scar biomechanics of CD8-/- mice demonstrated increased regional stiffness compared to WT mice. Re-supplementation with splenic CD8+ T-cells decreased scar tissue stiffness by more than 2-fold compared to vehicle treated CD8-/- mice, mimicking the biomechanics of WT mice. Ex-vivo GzmK demonstrated the ability to cleave collagen in a concentration and temporal-dependent manner. Cleavage of the collagen substrate was detected within a 6-hour period at GzmK concentrations as low as 50 nanomolar (nM), and as early as 2-hours at 100 nM. GzmK at a concentration of 100 nM demonstrated a 10-fold greater collagen cleavage capacity compared to GzmB at the same concentration suggesting that GzmK actions may be distinctly separate from that of GzmB in the post-MI setting.In conclusion, our data demonstrates that CD8+ T-cells regulate cardiac fibrosis likely through release of granzymes, leading to alterations in the biomechanical capability of the left ventricle. This project was funded by the National Institutes of Health T32GM123055, GM113278; the American Heart Association Innovator Project IPA35260039; the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award IK2BX003922; and South Carolina Translational Research Center UL1TR001450. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disorder and is characterized by autoantibody formation and subsequent immune complex deposition into target organs. SLE affects nearly nine women to every one man worldwide. Patients with SLE are at an enhanced risk for cardiovascular disease (CVD) morbidity and mortality. CVD is the leading cause of death worldwide and includes heart and blood vessel disorders, cerebrovascular disease, and rheumatic heart disease. Specific mechanisms by which cardiac and vascular pathophysiology develops in patients with SLE are still not fully known. Not only do we not understand this correlation between SLE and CVD, but there is also a critical gap in scientific knowledge on the contribution of sex. In this review, we will discuss the cardiac and vascular pathological disease states that are present in some patients with SLE. More importantly, we will discuss the potential mechanisms for the role of sex and sex hormones in the development of CVD with SLE.
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