A_2A Receptor Attenuates Hypertensive Cardiac Remodeling Via Promoting Brown Adipose Tissue-derived FGF21

Background:Hypertensive cardiac remodeling is characterized by interstitial fibrosis,which is essential pathological basis of cardiovascular events.Browning adipose tissue?BAT?is involved in the regulation of energy metabolism through non-shivering thermogenesis.It is also known that BAT-secreted adipokines also play an important protective role in cardiovascular diseases.Hypertension is normally associated with increased sympathetic activity and consequently can activate BAT.However,the precise mechanism underlying the interaction between BAT and cardiac remodeling is rarely investigated and remains elusive in hypertension.Recent studies revealed that Adenosine A_2A receptor(A_2AR)agonist could activate BAT,but the physiological and pathological function of A_2AR and BAT in hypertensive cardiac remodeling is still unclear.Objective:We aim to determine whether A_2AR could regulate hypertensive cardiac remodeling via activating BAT.To further investigate the detailed mechanisms underlying the endocrine role of BAT in pathological process of cardiac remodeling.Methods and Results:1.Effect of A_2AR on cardiac structure and function of hypertension:Wild type?WT?or A_2AR knockout(A_2ARKO)mice were randomly assigned to sham group or deoxycorticosterone acetat?DOCA?-salt group.A_2ARKO led to echocardiography detectable dysfunction in DOCA-salt-treated mice.Histological analysis indicated that A_2ARKO also reduced BAT activity in DOCA-salt group.In vitro,A_2AR agonist?CGS21680?or its antagonist?KW6002?had no directly effect on aldosterone-induced cardiac fibroblasts migration and proliferation.2.Effect of brown adipocyte-specific A_2ARKO on cardiac structure and function of hypertension:We generated brown adipocyte-specific A_2ARKO?BAAKO?mice treated with DOCA-salt to induce hypertension.BAAKO exacerbated hypertensive cardiac remodeling,as demonstrated by increased mRNA expression of hypertrophic markers?ANP,BNP and?MHC?and fibrotic makers?Col1a1,?SMA and TGF??.3.Effect of recombinant fibroblast growther factor 21?FGF21?protein on hypertensive cardiac remodeling:The interscapular BAT was surgically deleted and these mice were intraperitoneally injected with FGF21 for 14 days.FGF21administration rescued surgical BAT depletion-induced dramatic hypertensive cardiac remodeling.4.Effect of brown adipocyte-specific FGF21KO on hypertensive cardiac remodeling:Brown adipocyte-specific FGF21KO?BAFKO?mice and littermates were treated with CGS21680 or PBS.The protective effect of CGS21680 was nullified in BAFKO mice.5.AMPK/PGC1?pathway was involved in the expression and secretion of FGF21:At last,AMP-activated protein kinase?AMPK?inhibitor or lentivirus peroxisome proliferator-activated receptor?PPAR?-?coactivator?PGC1a?small interfering RNA?siRNA?were utilized to pretreat brown adipocytes.AMPK inhibitor and PGC1a siRNA both attenuated CGS21680-induced FGF21expression in brown adipocytes.Conclusions:1?A_2AR deficiency aggravated hypertensive cardiac remodeling and decreased BAT activity.2?A_2AR mediated FGF21 expression and secretion in BAT.3?AMPK/PGC1?pathway was involved in the FGF21 expression in brown adipocytes.