The mechanisms linking renin-angiotensin-aldosterone system (RAAS) to hypertrophy have not been fully established, but, Ang-(1-7)/Mas reticence and ovariectomy are important contributors. Interleukin cytokines and natriuretic peptides are key regulators of cardiac hypertrophy, lifting the possibility that hypertrophied persons have an impaired interleukins and natriuretic peptides levels. In the present novel study, FVB/N mouse model with Ang-(1-7) receptor Mas genetic deletion and ovariectomy was used to investigate function of renin-angiotensin-aldosterone system (RAAS) and estrogen in the molecular and endocrine control and regulation of cardiovascular homeostasis and to find their relationship with interleukin-1 and natriuretic peptide families and their receptors via using gender difference approach. - 64 - Immunohistochemical (IHC) and reverse transcription and quantitative real-time polymerase chain reaction (RT-PCR) analyses were performed, parallel relating morphological and histological findings. Histological and morphological analyses of heart revealed left ventricular hypertrophy in Ang-(1-7)/Mas-/- female mice (KF) in conjunction with significantly smaller BW (body weight), TL (tibia length), cardiomyocyte nuclei of left ventricle, ANP and NPRA receptor expression reflecting a significantly enlarged HW (heart weight), LV (left ventricle weight), HW/BW (heart weight-to-body weight) ratio, LV/BW (left ventricle-to-body weight) ratio, LV/TL (left ventricle-to-tibia length) ratio, cardiomyocyte diameter of left ventricle, interleukin-1 (alpha, beta, and IL1R1), and BNP expression levels compared to normal females (WF). Correspondingly, enlarged left ventricular hypertrophy in ovariectomized female mice (WFO) was illustrated from significantly higher BW (body weight), HW (heart weight), LV (left ventricle weight), TL (tibia length), cardiomyocyte diameter of left ventricle, interleukin-1 (alpha, beta, and IL1R1), and BNP expressions as well as a fewer cardiomyocyte nuclei of left ventricle, and significantly low expression of ANP, and NPRA levels compared to controls (WF). Ang-(1-7)-/- female mice following ovariectomy (KFO) resulted in significantly higher BW (body weight), TL (tibia length), cardiomyocyte nuclei of left ventricle, natriuretic peptides (BNP, ANP, and NPRA) expression with a significantly diminished HW (heart weight, mg), LV (left ventricle weight), LV/BW (left ventricle-to-body weight) ratio, LV/TL (left ventricle-to-tibia length) ratio, cardiomyocyte diameter of left ventricle, and significantly enlarged interleukin-1 (alpha, beta, and IL1R1) expression in left ventricle compared to Ang-(1-7)-/- females (KF). There was significant reduction in BW (body weight, gm), TL (tibia length, mm), and levels of BNP Ang-(1-7)-/- male (KM) as well as significantly enlarged HW (heart weight, mg), LV (left ventricle weight), LV/BW (left ventricle-to-body weight) ratio, LV/TL (left ventricle-to-tibia length) ratio, cardiomyocyte nuclei of left ventricle, ANP, NPRA, and interleukin-1 (alpha, beta, and IL1R1) expression levels compared to wild type male (WM) indicating left ventricular hyperplasia in Ang-(1-7)-/- male mice (KM) as compared to littermate controls (WM). - 65 - Moreover, wild type female FVB/N mice (WF) showed a significant diminished BW (body weight), TL (tibia length), HW (heart weight), LV (left ventricle weight), cardiomyocyte diameter of left ventricle, cardiomyocyte nuclei of left ventricle, BNP, NPRA, interleukin-1beta and IL1R1 expression in adding together to high ANP and interleukin-1alpha expression levels in comparison with wild type male mice (WM). Confirming our gender based model of cardiac hypertrophy, Ang-(1-7)-/- female mice (KF) had significantly smaller BW (body weight), TL (tibia length), HW (heart weight), cardiomyocyte nuclei of left ventricle, natriuretic peptides (BNP, ANP, and NPRA), interleukin-1beta and IL1R1 expression reflecting a significantly enlarged LV (left ventricle weight), LV/BW (left ventricle-to-body weight) ratio, LV/TL (left ventricle-to-tibia length) ratio, cardiomyocyte diameter of left ventricle, and interleukin-1alpha expression compared to Ang-(1-7)-/- male mice (KM). Consequently, together these findings point toward an individual key cardioprotective function of Ang-(1-7)/Mas and estrogen in restraint pathologic interleukin cytokines expression and augmentation of significant natriuretic peptides as a unique strategy to prevent functional left ventricular myocardium during onset of hypertrophy cascade in adult FVB/N mice.