Abstract 424: Cardiac Hypertrophy In Angiotensin Ii-dependent Hypertension: Dominant Effect Of Blood Pressure

Abstract

Left ventricular hypertrophy (LVH) is a common manifestation of end-organ injury in HTN. ACEi and ARBs attenuate the development of LVH through actions suggested to depend on direct interruption of AT1R in cardiac myocytes, rather than their effects to lower BP. In order to define the contribution of AT1R in cardiac myocytes to LVH, we made 2 mouse lines with cell-specific deletion of AT1AR from the heart using a floxed Agtr1a allele. In the 1st line, loss of AT1AR was achieved using a heterologous Cre transgene driven by the Sm22 promoter (Tagln-Cre) expressing Cre in VSMC and cardiac myocytes. There was virtually complete loss of AT1AR from cardiac myocytes and VSMCs in aorta, but not resistance vessels. Thus, with chronic AngII infusion, Tagln-KOs develop HTN to the same level as controls (MAP: 157±6 vs. 153±6 mm Hg, P=NS). In AngII-infused controls, there was cardiac oxidative stress indicated by enhanced nitrated tyrosine, but this was reduced by ≈75% in Tagln-KOs (P<0.005). Despite the absence of AT1AR in cardiac myocytes and differences in cardiac free radicals, the extent of cardiac hypertrophy was similar in Tagln-KOs and controls (6.9±0.2 vs. 6.7±0.2 mg/gm; P=NS). Similarly, myocardial BNP mRNA levels and the severity of cardiac injury were not reduced in Tagln-KOs compared to controls. Hence, the phenotype and molecular signature of LVH were not affected by the absence of cardiac AT1AR in Tagln-KOs. The 2nd mouse line of mice utilized a Cre cassette “knocked-in” to the Sm22 locus (KISm22-KOs). Like the Tagln-KOs, the KISm22-KOs exhibited elimination of AT1AR from cardiac myocytes and VSMCs in large arteries, but in this case AT1AR were also deleted from VSMCs in resistance vessels. Accordingly, Ang II-induced HTN was attenuated in KISm22-KOs (MAP: 122±3 vs. 145±4 mm Hg; P=0.004). Moreover, unlike the Tagln-KOs, cardiac hypertrophy was also diminished (5.5±0.2 vs. 7.4±0.6 mg/gm; p=0.01) and BNP mRNA levels were reduced (1.0±0.2 vs 2.6±0.8; p<0.05) compared to controls. In summary, in two models lacking AT1AR in the heart, the extent of cardiac hypertrophy in AngII HTN followed the BP, rather than AT1AR expression in cardiac myocytes. Our findings suggest the magnitude of BP elevation is of primary importance in driving the development of cardiac hypertrophy.