Age-related Clonal Hematopoiesis Predisposes To Hypertension In Mice Through An Inflammasome Mechanism

Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease (CVD). Clonal events in the hematopoietic system resulting from somatic mutations in “driver” genes such as Tet2 are prevalent in elderly individuals in the absence of overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (ARCH), and it is a newly recognized risk factor for CVD. It is unknown whether ARCH and hypertension in the elderly are causally related and, if so, what are the mechanistic features. Objective: Given that the aging process increases the prevalence of hypertension and ARCH, the current experimental study was designed to test the effect of ARCH in hypertension incidence. Methods and Results: A murine model of adoptive bone marrow transplantation to nonconditioned mice was employed to examine the interplay between ARCH and hypertension. Mice carrying Tet2-deficiency in hematopoietic cells resulted in elevated systolic (SBP) and diastolic blood pressure (DBP) as early as one day after challenge with a sub-pressure dose of angiotensin II (Ang II) 200ng/kg/min; SBP (day 1 Tet2 -/- : 148 mmHg± 4 vs. WT: 129±2 mmHg, P=0.002); day 9 Tet2 -/- 159±7 mmHg vs. WT: 139±5 mmHg, P<0.05), and DBP (day 1, Tet2 -/- : 108 ±3 mmHg vs. WT: 100±1 mmHg, P<0.005; day 9, Tet2 -/- : 111 ±4 mmHg vs. WT 107±3 mmHg). The ARCH Tet2 model of CH led to greater macrophage infiltration in the kidney, aorta and mesentery after Ang II compared with WT-treated mice. The Tet2-/- CH condition led to renal NLRP3 inflammasome activation and elevated renal levels of IL (interleukin)-1β (Tet2 -/- 1.4 vs. WT: 0.96, P<0.005) and IL-18 (Tet2 -/- 1.56 vs. WT: 1.18, P<0.005) after Ang II administration. Interestingly, administration of the inflammasome inhibitor MCC950 reversed hypertension seen in the mouse model of Tet2 -/- CH. Conclusion: Our data show that a sub-pressor dose of Ang II promotes hypertension due to elevated renal immune cell infiltration in a Tet2-CH model, promoting IL1-β and IL-18. These data suggest that Tet2 -/- CH carriers could be at elevated risk for the development of hypertension, and that NLRP3 inhibitors could be useful for treating hypertension in this population.