Calcineurin Activity in the Cardiac Left Ventricle of Transgenic AIDS mice that undergo experimental Myocardial Infarction: Experimental approaches to a new clinical problem Open Access

Jedrzejczak, Mark Justin (2015)

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In the era of antiretroviral therapy, the HIV population is living longer but becoming sick from diseases other than AIDS, so called HIV/AIDS non-AIDS diseases (HANA). Cardiovascular disease (CVD) is a HANA with increasing roles. The compensatory mechanisms for cardiac remodeling and hypertrophy are well characterized, but the role of HIV/AIDS in CVD is poorly understood. The protein phosphatase calcineurin (PPP3C) has been shown to activate nuclear factors of activated T-cells (NFATc) which initiate transcription of genes linked mechanistically to the development of left ventricle (LV) hypertrophy. Little is known about this canonical pathway in HIV/AIDS. To explore this relationship, transgenic mice (MSB) served as models of HIV/AIDS. MSB were subjected to myocardial infarct (MI) using ligation of a coronary artery ligation (CAL) to simulate the clinical event of cardiac ischemia. Alterations within the calcineurin-NFAT pathway were explored in this authentic HIV/AIDS models with MI. Expression of calcineurin and upstream signaling moieties were defined in murine LV samples by real-time PCR (qPCR) and analyzed statistically. Steady state polypeptide abundance was defined using SDS-PAGE Western blots while PPP3C phosphatase activity was assayed spectrophotometrically. qPCR data in MSB-CAL LVs showed decreased gene expression of relevant moieties in the calcineurin pathway including PI3KR1, PTEN, CAMK2D, CACNB2, CACNA2D1, CACNA1C, PKCB, CHP2, PPP3R1, PP3R2, PPP3CA, PPP3CB, PPP3CC, and RICTOR. Although polypeptide abundance remained unchanged, calcineurin activity in transgenic mice decreased twenty-four fold and activity in MSB-CAL mice exhibited a three-fold decrease. The consistent cellular changes in LVH signaling pathways have helped identify a previously unknown role of HIV/AIDS in MI.

Table of Contents

Introduction. 1

HIV/AIDS and Cardiovascular Disease. 1

Calcium signaling mechanisms. 1

Figure 1. 2

Calmodulin-mediated Calcineurin-NFAT hypertrophy pathway. 3

Role of Calcineurin in HIV and Heart Failure. 4

Methods. 5

Results. 8

Table 1. 12

Figure 2A. 13

Figure 2B. 14

Figure 2C. 14

Figure 2D. 15

Figure 3. 16

Figure 4. 17

Figure 5. 17

Figure 6. 18

Discussion. 19

Appendix. 22

References. 24

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