CD4+ Lymphocyte Regulation of Vascular and Cardiac Extracellular Matrix Structure and Function

Abstract

Cardiovascular disease, often induced by hypertension, represents a serious health threat, is a primary cause of death worldwide, and results in altered cardiovascular function and ECM composition. Hypertension and related cardiovascular diseases are associated with immune dysfunction. This dissertation investigated the role of T-lymphocytes in modulating cardiovascular function and ECM composition as a possible therapeutic for the treatment of cardiovascular disease. Study one investigated the role of TCR peptide in the development of hypertension and subsequent cardiovascular changes in Balb/C mice. The coadminstration of TCR and L-NAME/8% NaCl reduced the effects of L-NAME/8% NaCl, decreasing blood pressure and crosslinked collagen compared to L-NAME/8% NaCl alone. Study two examined the effects of T-lymphocyte function on cardiovascular structure and function. Adoptive transfer of T-lymphocytes from C57BL/6 WT mice into C57BL/6 SCID mice induced changes in the SCID so that it resembled the WT donor, with increased percent crosslinked collagen and LOX activity. Hemodynamics in the SCID recipient resembled that of the WT and were significantly different from the sham injected SCID. Study three combined aspects of both previous studies. T-lymphocytes were adoptively transferred from hypertensive WT donors into naïve SCID recipients, who developed hypertension and cardiovascular function resembling the hypertensive donor, as well as changes in the ECM, including increased collagen crosslinking. Study four investigated the effect of strain specific T-lymphocyte polarization on hypertension induced cardiac ECM remodeling. Balb/C, C57BL/6 WT, and C57BL/6 SCID had divergent responses to L-NAME induced hypertension. Ventricular stiffness increased in Balb/C, decreased in C57 SCID and did not change in C57 WT; LOX activity changed correspondingly in all groups. The final study examined the effect of TCR administration on LOX activity and collagen crosslinking. Th1 polarization increased LOX activity and crosslinked collagen with corresponding changes in cardiovascular function. In conclusion, modulation of T-lymphocyte function alters cardiovascular function and ECM composition in pathologic and non-pathologic conditions. Immune modulation should be further investigated as a therapeutic for cardiovascular disease.