The Effects of Dopamine Receptor D3 Deficiency in Age‐dependent Left Ventricular Remodeling

Abstract

Aging is an independent risk factor for cardiovascular disease. Additionally, normal aging associates with a decrease on the levels of the neuromodulator dopamine (DA). While the role of DA in the pathophysiology of hypertension and in autonomic function is well‐established in young animals, much less is known on how DA levels and signaling affect cardiac aging. Decreased receptor expression/function of the D2‐like DA receptor family (DRD2 and DRD3) have been implicated in the development of renal and cardiac fibrosis. It is well established that myocardial aging is characterized by left ventricular (LV) fibrosis, which is a component of LV adverse remodeling. Accordingly, the goal of this study was to elucidate the effects of DRD3 deficiency in age‐dependent LV remodeling.MethodsWe used 3, 6, 12, and 18 month old (m.o.) wild type (WT) and DRD3 knockout (D3KO) male and female mice (n=6/sex/age/genotype). Cardiac function was assessed by serial echocardiography, and plasma and left ventricle were harvested to analyze molecular parameters of LV remodeling, particularly extracellular matrix composition.ResultsEchocardiography analysis demonstrated that D3KO mice have a continuous, age‐dependent, increase of the LV anterior wall (LVAW), compared to WT, in both genders, but more markedly in females. This suggests that female D3DKO may have age‐dependent hypertrophy. In addition, the interior diameter in diastole (LVIDd) of D3KO animals was consistently smaller than WT mice of the same age, particularly at 6 and 12 m.o. (Figure 1). Cardiac fibrosis increased in the older male animals (18 m.o.) compared to all other ages in both genotypes. Females, however, showed a distinct genotype‐dependent pattern, suggesting sex‐differences in collagen metabolism with age. Genes associated with cardiac remodeling, as Gsta1, Nrp2, Mmp12 and Vcam1 showed increased expression with aging in WT females, but not in D3KO. Male D3KO however, displayed increased Ccl2 and Ecm1 at 18 m.o. compared to all other ages and Casp1 (an inflammatory response initiator) was increased in D3KO with time.ConclusionOur data suggests that DRD3 function in the heart plays an important gender‐specific role in age‐dependent cardiac remodeling.Support or Funding InformationWe acknowledge support from American Heart Association (14SDG18860050) and the Research and Graduate School at East Carolina University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.