Key result
Complete disruption of all three nitric oxide synthase genes in mice resulted in left ventricular hypertrophy and diastolic dysfunction, which was prevented by an AT1 receptor blocker.
Why the study?
Does an angiotensin II type 1 (AT1) receptor blocker prevent left ventricular hypertrophy and diastolic dysfunction in triple n/i/eNOS(-/-) mice?
Does an angiotensin II type 1 (AT1) receptor blocker prevent left ventricular hypertrophy and diastolic dysfunction in triple n/i/eNOS(-/-) mice?
Answers are grounded in this paper and cite their sources.
In a mouse model lacking all three nitric oxide synthase isoforms, the AT1 receptor pathway plays a central role in the pathogenesis of left ventricular hypertrophy and diastolic dysfunction.
Nitric oxide (NO) is synthesized by three distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human heart. The roles of NOSs in the pathogenesis of heart failure have been described in pharmacological studies with NOS inhibitors. Recently, genetically engineered animals have been used. We have generated mice in which all 3 NOS isoforms are completely disrupted (triple n/i/eNOS(-/-) mice). Morphological, echocardiographic, and hemodynamic analysis were performed in wild-type, singly nNOS(-/-), iNOS(-/-), eNOS(-/-), and triple n/i/eNOS(-/-) mice. Importantly, significant left ventricular (LV) hypertrophy and diastolic dysfunction was noted only in n/i/eNOS(-/-) mice, and those pathology was similar to diastolic heart failure in humans. Finally, treatment with an angiotensin II type 1 (AT1) receptor blocker, significantly prevented those abnormalities. These results provide the evidence that AT1 receptor pathway plays a center role in the pathogenesis of cardiac disorders in the n/i/eNOS(-/-) mice. Our studies with triple n/i/eNOS(-/-) mice provide pivotal insights into an understanding of the pathophysiology of NOSs in human heart failure.
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Shibata et al. (2013) conducted a review in Heart failure. Nitric oxide synthase gene deletion vs. Wild-type mice was evaluated. Complete disruption of all three nitric oxide synthase genes in mice resulted in left ventricular hypertrophy and diastolic dysfunction, which was prevented by an AT1 receptor blocker.
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